
Cysteine
RESEARCH REPORTS
FROM MEDLINE
Database
Click on the
image to go to the page which links to all the other pages on this web site on the subject
of "oral chelation." Cysteine is the most important ingredient in our Oral
Chelation formula.
This page contains about 160 out of 286 research reports
searching on the two words: "cysteine" and "toxic." As you
read these reports you will find, generally, that cysteine has the ability to reduce
toxicity. In most cases the word "cysteine" has been made BOLD to facilitate
finding it in the abstracts and titles.
Some of these reports are classified as REVIEW and are generally
easier to understand. The Review reports, also, usually summarize many other
studies. There are about 40 of these Review reports on this same page. Click Here to go immediately to the Review Reports.
Finally, these reports are written in the very formal language
of research scientisists. You will not particularly find them easy to read unless
you have technical training. But, it is worth the effort if you want to become
comfortable with the incredible claims made by Vibrant Life about the oral chelation
formula available to purchase on this web site. Virtually no other company has done
the research on cysteine -- and then put together a formula to prevent heart disease and
reverse its symptoms. If you do want to study this ingredient, you might find a table of definitions and terms helpful.
TOP
| Number |
Title |
Comments |
| ...0... |
Differential modulation of the uptake currents by redox
interconversion of cysteine residues in the human neuronal glutamate
transporter EAAC1. |
The redox interconversion of cysteines induced by
dithiothreitol/DTNB
influenced the Vmax (Imax) of transport, while the apparent affinity for glutamate was not
affected. Formation or breakdown of disulphide groups did not affect the pre-steady-state
currents, suggesting that these manipulations do not interfere with the Na+
binding/unbinding and/or the charge distribution on the transporter molecule.
|
| ...1... |
Renal cysteine conjugate beta-lyase-mediated
toxicity studied with primary cultures of human proximal tubular cells. |
|
| ...2... |
ICE-protease inhibitors block murine liver injury and
apoptosis caused by CD95 or by TNF-alpha. |
|
| ...3... |
Mitochondrial bioactivation of cysteine
S-conjugates and 4-thiaalkanoates: implications for mitochondrial dysfunction and
mitochondrial diseases. |
|
| ...4... |
Cellular effects of reactive intermediates: nephrotoxicity of
S-conjugates of amino acids. |
|
| ...5... |
Disease-modifying antirheumatic drugs, including methotrexate,
sulfasalazine, gold, antimalarials, and penicillamine. |
|
| ...6... |
Disease-modifying antirheumatic drugs, including methotrexate,
gold, antimalarials, and D-penicillamine. |
|
| ...7... |
Cysteine protects Na,K-ATPase and isolated
human lymphocytes from silver toxicity. |
|
| ...8... |
Apoptosis in Burkitt lymphoma cells is prevented by promotion
of cysteine uptake. |
|
| ...9... |
Role of the disulfide bond in Shiga toxin A-chain for toxin
entry into cells. |
|
| ..10... |
Bioactive organosulfur phytochemicals in Brassica oleracea
vegetables--a review. |
|
| ..11... |
Proteolytically active 2A proteinase of human rhinovirus 2 is
toxic for Saccharomyces cerevisiae but does not cleave the homologues of eIF-4 gamma in
vivo or in vitro. |
|
| ..12... |
Decreased cysteine and glutathione levels:
possible determinants of liver toxicity risk in Ghanaian subjects. |
|
| ..13... |
Streptococcal pyrogenic exotoxin A, streptolysin O,
exoenzymes, serotype and biotype profiles of Streptococcus pyogenes isolates from patients
with toxic shock syndrome and other severe infections. |
|
| ..14... |
Biotransformation of trichloroethene: dose-dependent excretion
of 2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation. |
|
| ..15... |
Inhibition of the conversion of pre-interleukins-1 alpha and 1
beta to mature cytokines by p-benzoquinone, a metabolite of benzene. |
|
| ..16... |
Excretion of N-acetyl-S-(1-phenyl-2-hydroxyethyl)-cysteine
and N-acetyl-S-(2-phenyl-2-hydroxyethyl)-cysteine in workers exposed to
styrene. |
|
| ..17... |
Poliovirus 2Apro expression inhibits growth of yeast cells. |
|
| ..18... |
Expression and characterization of group A Streptococcus
extracellular cysteine protease recombinant mutant proteins and
documentation of seroconversion during human invasive disease episodes. |
|
| ..19... |
Depletion of total cysteine, glutathione, and
homocysteine in plasma by ifosfamide/mesna therapy. |
|
| ..20... |
CPP32 inhibition prevents Fas-induced ceramide generation and
apoptosis in human cells. |
|
| Menu Position #20 |
| ..21... |
Modulation of radiation-induced apoptosis by thiolamines. |
|
| ..22... |
The role of glutathione conjugation in the development of
kidney tumours in rats exposed to trichloroethylene. |
|
| ..23... |
Processing/activation of at least four interleukin-1beta
converting enzyme-like proteases occurs during the execution phase of apoptosis in human
monocytic tumor cells. |
|
| ..24... |
The function of gamma-glutamyl transpeptidase as a determinant
in cell sensitivity to azaserine toxicity. |
|
| ..25... |
Collagenase inhibitors: rationale for their use in treating
corneal ulceration. |
|
| ..26... |
Apoptosis and necrosis in toxicology: a continuum or distinct
modes of cell death? |
|
| ..27... |
No-induced oxidative stress and glutathione metabolism in
rodent and human cells. |
|
| ..28... |
Comparison of sulfur amino acid utilization for GSH synthesis
between HepG2 cells and cultured rat hepatocytes. |
|
| ..29... |
Cleavage of the human C5A receptor by proteinases derived from
Porphyromonas gingivalis: cleavage of leukocyte C5a receptor. |
|
| ..30... |
Glutathione transferase activity and formation of
macromolecular adducts in two cases of acute methyl bromide poisoning. |
|
| ..31... |
Elevation of homocysteine and excitatory amino acid
neurotransmitters in the CSF of children who receive methotrexate for the treatment of
cancer. |
|
| ..32... |
Glutathione deficiency in alcoholics: risk factor for
paracetamol hepatotoxicity. |
|
| ..33... |
Oxidative stress and thiol depletion in plasma and peripheral
blood lymphocytes from HIV-infected patients: toxicological and pathological implications.
|
|
| ..34... |
Differential activity of bcl-2 and ICE enzyme family protease
inhibitors on Fas and puromycin-induced apoptosis of glioma cells. |
|
| ..35... |
N-acetylcysteine treatment and the risk of toxic reactions to
trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected
patients. |
|
| ..36... |
Activity and distribution of the cysteine
prodrug activating enzyme, 5-oxo-L-prolinase, in human normal and tumor tissues. |
|
| ..37... |
Glutathione in human melanoma cells. Effects of cysteine,
cysteine esters and glutathione isopropyl ester. |
|
| ..38... |
Looking beneath the surface: the cell death pathway of
Fas/APO-1 (CD95). |
|
| ..39... |
Human rhinovirus 2A proteinase mutant and its second-site
revertants. |
|
| ..40... |
Effect of selenium compounds and thiols on human mammary tumor
cells. |
|
| Menu Position #40 |
| ..41... |
D-Penicillamine induced toxicity in rheumatoid arthritis: the
role of sulphoxidation status and HLA-DR3. |
|
| ..42... |
The influence of the protector thiol L-cystein on the toxic
and therapeutic responses of stabilized "activated" cyclophosphamide
(4-(S-ethanol)-sulfido-cyclophosphamide). |
|
| ..43... |
Neuronal nitric oxide synthase, a modular enzyme formed by
convergent evolution: structure studies of a cysteine thiolate-liganded
heme protein that hydroxylates L-arginine to produce NO. as a cellular signal [published
erratum appears in FASEB J 1996 Jul;10(9):1107] |
|
| ..44... |
Interleukin-1beta secretion is impaired by inhibitors of the
Atp binding cassette transporter, ABC1. |
|
| ..45... |
Modulation of gene expression in subjects at risk for
colorectal cancer by the chemopreventive dithiolethione oltipraz. |
|
| ..46... |
High-dose intravenous glutathione in man. Pharmacokinetics and
effects on cyst(e)ine in plasma and urine. |
|
| ..47... |
Influence of combined use of selenious acid and SH compounds
in parenteral preparations. |
|
| ..48... |
Looking beneath the surface: the cell death pathway of
Fas/APO-1 (CD95). |
|
| ..49... |
Human rhinovirus 2A proteinase mutant and its second-site
revertants. |
|
| ..50... |
Effect of selenium compounds and thiols on human mammary tumor
cells. |
|
| ..51... |
D-Penicillamine induced toxicity in rheumatoid arthritis: the
role of sulphoxidation status and HLA-DR3. |
|
| ..52... |
The influence of the protector thiol L-cystein on the toxic
and therapeutic responses of stabilized "activated" cyclophosphamide
(4-(S-ethanol)-sulfido-cyclophosphamide). |
|
| ..53.. |
Neuronal nitric oxide synthase, a modular enzyme formed by
convergent evolution: structure studies of a cysteine thiolate-liganded
heme protein that hydroxylates L-arginine to produce NO. as a cellular signal [published
erratum appears in FASEB J 1996 Jul;10(9):1107] |
|
| ..54... |
Interleukin-1beta secretion is impaired by inhibitors of the
Atp binding cassette transporter, ABC1. |
|
| ..55... |
Modulation of gene expression in subjects at risk for
colorectal cancer by the chemopreventive dithiolethione oltipraz. |
|
| ..56... |
High-dose intravenous glutathione in man. Pharmacokinetics and
effects on cyst(e)ine in plasma and urine. |
|
| ..57... |
Influence of combined use of selenious acid and SH compounds
in parenteral preparations. |
|
| ..58... |
S. cerevisiae and sulfur: a unique way to deal with the
environment. |
|
| ..59... |
S-phenylcysteine in albumin as a benzene biomarker. |
|
| ..60... |
Copper ions differ from other thiol reactive metal ions in
their effects on the concentration and redox status of thiols in HeLa cell cultures. |
|
| Menu Position #60 |
| ..61... |
Cysteine concentrations in rodent tumors:
unexpectedly high values may cause therapy resistance. |
|
| ..62... |
Protective action of ascorbic acid and sulfur compounds
against acetaldehyde toxicity: implications in alcoholism and smoking. |
|
| ..63... |
Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's
disease. |
|
| ..64... |
Inhibition of human leukaemia 60 cell growth by
S-D-lactoylglutathione in vitro. Mediation by metabolism to N-D-lactoylcysteine and
induction of apoptosis. |
|
| ..65... |
The cell-damaging effects of low amounts of homocysteine and
copper ions in human cell line cultures are caused by oxidative stress. |
|
| ..66... |
Amyotrophic lateral sclerosis: fasting plasma levels of cysteine
and inorganic sulfate are normal, as are brain contents of cysteine [see
comments] |
|
| ..67... |
Ethanol decreases plasma sulphydryls in man: effect of
disulfiram. |
|
| ..68... |
Apoptotic cell death induced by serum and its prevention by
thiols. |
|
| ..69... |
Glutathione metabolism and its role in hepatotoxicity. |
|
| ..70... |
Perchloroethylene-induced rat kidney tumors: an investigation
of the mechanisms involved and their relevance to humans. |
|
| ..71... |
Inhibition of adenovirus infection with protease inhibitors. |
|
| ..72... |
Augmentation of CD8 and CD4 lymphocytes subsets in AIDS
infected children after treatment with a non-toxic chelating agents compound--Rodilemid. |
|
| ..73... |
Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's
disease. |
|
| ..74... |
Inhibition of human leukaemia 60 cell growth by
S-D-lactoylglutathione in vitro. Mediation by metabolism to N-D-lactoylcysteine and
induction of apoptosis. |
|
| ..75... |
The cell-damaging effects of low amounts of homocysteine and
copper ions in human cell line cultures are caused by oxidative stress. |
|
| ..76... |
Amyotrophic lateral sclerosis: fasting plasma levels of cysteine
and inorganic sulfate are normal, as are brain contents of cysteine [see
comments] |
|
| ..77... |
Ethanol decreases plasma sulphydryls in man: effect of
disulfiram. |
|
| ..78... |
Apoptotic cell death induced by serum and its prevention by
thiols. |
|
| ..79... |
Glutathione metabolism and its role in hepatotoxicity. |
|
| ...80... |
Perchloroethylene-induced rat kidney tumors: an investigation
of the mechanisms involved and their relevance to humans. |
|
| Menu Position #80 |
| ..91... |
Central nervous system cytokines and their relevance for
neurotoxicity and apoptosis. |
|
| ..92... |
Degradation of oxidized proteins in mammalian cells. |
|
| ..93... |
Chelation of mercury by polymercaptal microspheres: new
potential antidote for mercury poisoning. |
|
| ..94... |
Bcl-2 prevents nitric oxide-mediated apoptosis and
poly(ADP-ribose) polymerase cleavage. |
|
| ..95... |
Chemical debridement of burns: mercaptans. |
|
| ..96... |
Role of superoxide and hydrogen peroxide in cell lysis during
irradiation in vitro of Ehrlich ascitic carcinoma cells in the presence of melanin. |
|
| ..97... |
The disposition of paracetamol and its conjugates during
multiple dosing in patients with end-stage renal failure maintained on haemodialysis. |
|
| ..98... |
Thiol status and cytopathological effects of acrolein in
normal and xeroderma pigmentosum skin fibroblasts. |
|
| ..99... |
Homocysteine levels in patients with rheumatoid arthritis
treated with low-dose methotrexate. |
|
| .100... |
Development of low- and high-serum culture conditions for use
of human oral fibroblasts in toxicity testing of dental materials. |
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| ..101... |
Cadmium resistance in A549 cells correlates with elevated
glutathione content but not antioxidant enzymatic activities. |
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Thiol status and cytopathological effects of acrolein in
normal and xeroderma pigmentosum skin fibroblasts. |
|
| ..103... |
The total free radical trapping ability of blood plasma in |
"The central conclusion from this work is that for
patients with eclampsia, the plasma concentrations of the essential nutrients: vitamin E,
vitamin C, and cysteinerich protein are too low for optimal antioxidant systems
activities." |
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Table Of Definitions And
Terms
| Word or phrase |
Definition |
Where Located |
| Food |
|
|
| Protein |
|
|
| Carbohydrate |
|
|
| Fat |
|
|
| Amino Acid |
|
|
| Eight Essential Amino Acids |
|
|
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Record #0
Title
- Differential modulation of the uptake currents by redox interconversion of cysteine
residues in the human neuronal glutamate transporter EAAC1.
- Author
- Trotti D; Nussberger S; Volterra A; Hediger MA
- Address
- Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston,
MA 02115, USA.
- Source
- Eur J Neurosci, 1997 Oct, 9:10, 2207-12
- Abstract
- Control of extrasynaptic glutamate concentration in the central nervous system is an
important determinant of neurotransmission and excitotoxicity. Mechanisms that modulate
glutamate transporter function are therefore critical factors in these processes. The
redox modulation of glutamate uptake was examined by measuring transporter-mediated
electrical currents and radiolabelled amino acid influx in voltage-clamped Xenopus oocytes
expressing the human neuronal glutamate transporter EAAC1. Up and down changes of the
glutamate uptake currents in response to treatment with dithiothreitol and
5,5'-dithio-bis-(2-nitrobenzoic) acid (DTNB) were observed in oocytes clamped at -60 mV.
The redox interconversion of cysteines induced by dithiothreitol/DTNB
influenced the Vmax (Imax) of transport, while the apparent affinity for glutamate was not
affected. Formation or breakdown of disulphide groups did not affect the pre-steady-state
currents, suggesting that these manipulations do not interfere with the Na+
binding/unbinding and/or the charge distribution on the transporter molecule. The
glutamate-evoked net uptake current of EAAC1 was composed of the inward current from
electrogenic glutamate transport and the current arising from the glutamate-activated Cl-
conductance. The structural rearrangement produced by the formation or breakdown of
disulphide groups only affected the current from electrogenic glutamate transport. The
electrogenic currents of EAAC1 were significantly reduced by peroxynitrite, an
endogenously occurring oxidant formed in certain pathological brain processes, and the
mechanism of inhibition partially depended on the formation of disulphide groups.
- Language of Publication
- English
- Unique Identifier
- 98081534
-
Record 1 from database: MEDLINE
Return To Top
- Title
- Renal cysteine conjugate beta-lyase-mediated toxicity studied with
primary cultures of human proximal tubular cells.
- Author
- Chen JC; Stevens JL; Trifillis AL; Jones TW
- Address
- Department of Pathology, University of Maryland School of Medicine, Baltimore 21201.
- Source
- Toxicol Appl Pharmacol, 1990 May, 103:3, 463-73
- Abstract
- The beta-lyase pathway has been shown to mediate the nephrotoxicity of S-cysteine
conjugates of a variety of haloalkenes in a number of animal models in vitro and in vivo.
However, there is no information available concerning this mechanism of bioactivation in
human tissues. In this investigation a well-characterized model of human proximal tubule
epithelial cells, the presumed target cell, was used to investigate the toxicity of a
series of glutathione and cysteine conjugates of nephrotoxic haloalkenes.
Both S-(1,2-dichlorovinyl)-glutathione (DCVG) and S-(1,2-dichlorovinyl)-L-cysteine
(DCVC) caused dose-dependent toxicity over a range of 25 to 500 microM. DCVC was
consistently found to be more toxic than DCVG, but the inclusion of
gamma-glutamyltransferase (0.5 U/ml) increased the toxicity of DCVG to that observed with
an equimolar concentration of DCVC, indicating that metabolism to the cysteine
conjugate is an important rate-limiting step in this in vitro model.
S-(1,2,3,4,4-Pentachlorobutadienyl)-L-cysteine,
S-(2-chloro-1,1,2-trifluoroethyl)-L-cysteine, and
S-(1,1,2,2-tetrafluoroethyl)- L-cysteine were also found to be toxic to
human proximal tubular cells. Incubation with [35S]DCVC resulted in covalent binding of
35S-label, which increased linearly to a final level of 1.05 nmol/mg protein at 6 hr.
Aminooxyacetic acid (250 microM), an inhibitor of pyridoxal phosphate-dependent enzymes
such as beta-lyase, protected the cells from the toxicity of all of the cysteine
conjugates and inhibited the covalent binding of 35S-label from [35S]DCVC to cellular
macromolecules. The results of the present study provide the first evidence that human
proximal tubular cells are sensitive to the toxicity of glutathione and/or cysteine
conjugates of a variety of chloro- and fluoroalkenes which are activated via the
beta-lyase pathway. The implications for human health are discussed.
- Language of Publication
- English
- Unique Identifier
- 90252220
- MeSH Heading (Major)
- Kidney Tubules, Proximal|CY/*EN; Lyases|*ME
- MeSH Heading
- Adolescence; Adult; Aminooxyacetic Acid|ME; Butadienes|TO; Cells, Cultured; Child; Cysteine|AA/TO;
Dose-Response Relationship, Drug; Epithelium|CY; Female; Glutathione|AA/TO; Human;
Hydrocarbons, Fluorinated|TO; Male; Middle Age; Structure-Activity Relationship; Support,
Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0041-008X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 4. (Lyases); EC 4.4.1.6 (S-alkylcysteine lyase); 0 (Butadienes); 0 (Hydrocarbons,
Fluorinated); 4371-52-2 (Cysteine); 627-72-5 (S-(1,2-dichlorovinyl)cysteine);
645-88-5 (Aminooxyacetic Acid); 70-18-8 (Glutathione); 87619-82-7
(S-pentachlorobuta-1,3-dien-yl-cysteine); 94840-66-1
(S-(1,1,2,2-tetrafluoroethyl)cysteine); 96563-01-8
(S-(2-chloro-1,1,2-trifluoroethyl)cysteine); 96614-59-4
(S-(1,2-dichlorovinyl)glutathione)
Record 2 from database: MEDLINE
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- Title
- ICE-protease inhibitors block murine liver injury and apoptosis caused by CD95 or by
TNF-alpha.
- Author
- Künstle G; Leist M; Uhlig S; Revesz L; Feifel R; MacKenzie A; Wendel A
- Address
- Department of Biochemical Pharmacology, Faculty of Biology, University of Konstanz,
Germany.
- Source
- Immunol Lett, 1997 Jan, 55:1, 5-10
- Abstract
- The two apoptosis receptors of mammalian cells, i.e. the 55 kDa TNF receptor (TNF-R1)
and CD95 (Fas/APO1) are activated independently of each other, however, their signaling
involves a variety of ICE-related proteases [I]. We used a cell-permeable inhibitor of
ICE-like protease activity to examine in vivo whether post-receptor signaling of TNF and
CD95 are fully independent processes. Mice pretreated with the inhibitor,
Z-VAD-fluoromethylketone (FMK) were dose-dependently protected from liver injury caused by
CD95 activation as determined by plasma alanine aminotransferase and also from hepatocyte
apoptosis assessed by DNA fragmentation (ID50 = 0.1 mg/kg). A dose of 10 mg/kg protected
mice also from liver injury induced by TNF-alpha. Similar results were found when
apoptosis was initiated via TNF-alpha or via CD95 in primary murine hepatocytes (IC50 =
1.5 nM) or in various human cell lines. In addition to prevention, an arrest of cell death
by Z-VAD-FMK was demonstrated in vivo and in vitro after stimulation of apoptosis
receptors. These findings show in vitro and in vivo in mammals that CD95 and the TNF-alpha
receptor share a distal proteolytic apoptosis signal.
- Language of Publication
- English
- Unique Identifier
- 97247751
- MeSH Heading (Major)
- Amino Acid Chloromethyl Ketones|PD/*TU; Antigens, CD95|*PH; Apoptosis|*DE; Cysteine
Proteinase Inhibitors|PD/*TU; Cysteine Proteinases|*PH; Hepatitis,
Toxic|*PC/PP; Liver|CY/*DE; Tumor Necrosis Factor|*TO
- MeSH Heading
- Alanine Transaminase|BL; Animal; Antigens, CD|DE/PH; Carcinoma, Hepatocellular|PA;
Cells, Cultured; DNA Fragmentation; Hela Cells|DE; Human; Interleukin-1|SE; Leukemia,
T-Cell, Acute|PA; Lipopolysaccharides; Liver Neoplasms|PA; Male; Mice; Mice, Inbred BALB
C; Receptors, Tumor Necrosis Factor|DE/PH; Support, Non-U.S. Gov't; Tumor Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0165-2478
- Country of Publication
- NETHERLANDS
Record 3 from database: MEDLINE
-
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- Title
- Mitochondrial bioactivation of cysteine S-conjugates and
4-thiaalkanoates: implications for mitochondrial dysfunction and mitochondrial diseases.
- Author
- Anders MW
- Address
- Department of Pharmacology, University of Rochester, New York 14642, USA.
- Source
- Biochim Biophys Acta, 1995 May, 1271:1, 51-7
- Abstract
- The toxicity of most drugs and chemicals is associated with their enzymatic conversion
to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles,
including mitochondria. The toxicity of haloalkene-derived cysteine
S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial
bioactivation. Toxic cysteine S-conjugates are formed by the glutathione
S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione
S-conjugates, which are hydrolyzed by gamma-glutamyltransferase and dipeptidases.
Mitochondrial cysteine conjugate beta-lyase-catalyzed bioactivation of cysteine
S-conjugates affords unstable alpha-halothiolates. Haloalkene-derived 4-thiaalkanoates,
which are analogs of cysteine S-conjugates that lack an alpha-amino
group, undergo bioactivation by the enzymes of fatty acid beta-oxidation to give
3-hydroxy-4-thiaalkanoates that eliminate alpha-halothiolates. alpha-Halothiolates yield
alkylating and acylating agents that interact with cellular macromolecules and thereby
cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine
S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine
nucleotide concentrations, depletion of the mitochondrial glutathione content,
perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are
seen with cysteine S-conjugates. Similar changes are observed with
cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and
hypoglycemia are also observed.
- Language of Publication
- English
- Unique Identifier
- 95322492
- MeSH Heading (Major)
- Cysteine|AA/*ME; Hydrocarbons, Halogenated|*ME/*TO; Mitochondria|*ME;
Mitochondrial Myopathies|*ME; Organelles|*ME
- MeSH Heading
- Animal; Biotransformation; Glutathione Transferase|ME; Human; Microsomes|ME; Oxidative
Phosphorylation|DE; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0006-3002
- Country of Publication
- NETHERLANDS
Record 4 from database: MEDLINE
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- Title
- Cellular effects of reactive intermediates: nephrotoxicity of S-conjugates of amino
acids.
- Author
- Anders MW; Elfarra AA; Lash LH
- Address
-
- Source
- Arch Toxicol, 1987, 60:1-3, 103-8
- Abstract
- Several cysteine S-conjugates are potent nephrotoxins and require
enzymatic activation to produce cytotoxicity. Strategies based on the knowledge that renal
cysteine conjugate beta-lyase is apparently a pyridoxal phosphate
(PLP)-dependent enzyme have been exploited to test the hypothesis that a
beta-lyase-dependent activation is required for the expression of cysteine
S-conjugate-induced toxicity. First, the toxicity of the model conjugate
S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is blocked both in vivo and in
isolated, renal proximal tubular cells by aminooxyacetic acid, an inhibitor of
PLP-dependent enzymes. Second, the nonmetabolizable alpha-methyl analogue
S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine is not toxic. Third, to test the hypothesis
that the toxicity of DCVC is associated with the metabolic formation of a reactive thiol,
S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC), which may undergo a PLP-dependent
gamma-elimination reaction to produce an identical thiol, was studied. DCVHC is a potent
nephrotoxin, and, similar to DCVC, its toxicity was blocked by aminooxyacetic acid and the
alpha-methyl analogue S-(1,2-dichlorovinyl)-DL-alpha-methylhomocysteine was not toxic.
Moreover, exposure of renal proximal tubular cells to propargylglycine, a suicide
substrate for PLP-dependent enzymes that catalyze gamma-elimination reactions, blocked the
toxicity of DCVHC. Fourth, the renal mitochondrial beta-lyase is localized in the outer
membrane; therefore, although DCVC was toxic to mitochondria, no toxicity was produced in
mitoplasts, which shows that a suborganelle site of activation is involved in the
mitochondrial toxicity of DCVC. Finally, the toxicity of both DCVC and DCVHC was blocked
by probenecid, indicating a role for the anion transport system. DCVC and DCVHC inhibit
cellular and mitochondrial respiration, indicating that mitochondria are primary
intracellular targets for nephrotoxic S-conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)
- Language of Publication
- English
- Unique Identifier
- 87297915
- MeSH Heading (Major)
- Amino Acids|*TO; Cell Survival|*DE; Kidney Diseases|*CI
- MeSH Heading
- Animal; Cysteine|TO; Human; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0340-5761
- Country of Publication
- GERMANY, WEST
- CAS Registry/EC Number
- 0 (Amino Acids); 4371-52-2 (Cysteine)
Record 5 from database: MEDLINE
Return To Top
- Title
- Disease-modifying antirheumatic drugs, including methotrexate, sulfasalazine, gold,
antimalarials, and penicillamine.
- Author
- Girgis L; Conaghan PG; Brooks P
- Address
- St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
- Source
- Curr Opin Rheumatol, 1994 May, 6:3, 252-61
- Abstract
- Recently, there has been an interest in rethinking the classification of antirheumatic
drugs. Emphasis continues to be on aggressive control of inflammation in the early phase
of rheumatoid arthritis. The mistake of extrapolating short-term clinical trial results to
long-term outcomes has been appreciated, pointing to the need for long-term studies.
Interest in the role of cytokines and their receptors in the inflammatory process
continues, as well as in the cellular mechanisms of action of the various
disease-modifying antirheumatic drugs (DMARDs). Troublesome toxicity profiles continue to
be reported, and a consideration of efficacy-toxicity trade-offs are important.
Methotrexate still shows long-term efficacy, and low-dose folinic acid has been shown to
reduce toxicity but not efficacy. New information on other DMARDs is presented, ie,
sulfasalazine inhibition of signal transduction, the effects of hydroxychloroquine on
cytokines and lipid metabolism, and the immunosuppressive effects of bucillamine, a
penicillamine-related compound.
- Language of Publication
- English
- Unique Identifier
- 94338857
- MeSH Heading (Major)
- Antimalarials|AE/*TU; Arthritis, Rheumatoid|*DT; Gold|AE/*TU; Methotrexate|AE/*TU;
Penicillamine|AE/*TU; Sulfasalazine|AE/*TU
- MeSH Heading
- Age Factors; Clinical Trials; Cysteine|AA/AE/TU; Gastrointestinal
System|DE; Human; Liver|DE
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1040-8711
- Country of Publication
- UNITED STATES
Record 6 from database: MEDLINE
-
Return To Top
- Title
- Disease-modifying antirheumatic drugs, including methotrexate, gold, antimalarials, and
D-penicillamine.
- Author
- Conaghan PG; Brooks P
- Address
- University of New South Wales, St. Vincent's Hospital, Darlinghurst, Australia.
- Source
- Curr Opin Rheumatol, 1995 May, 7:3, 167-73
- Abstract
- Recent literature continues to promote the early use of disease-modifying antirheumatic
drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of
combination DMARD treatments have been disappointing, and careful attention must be paid
to clinical trial design if the efficacy of combination therapies is to be established.
Methotrexate retains its prominent role, and its mechanism of action has been the subject
of many reports; its toxicity remains the most common reason for treatment termination.
Guidelines for monitoring hepatic toxicity of methotrexate have been published and may
help reduce the need for invasive biopsy procedures. Significant risk factors for
methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled
studies of both sulfasalazine and hydroxychloroquine have been reported and have
demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis.
Awareness of drug-toxicity profiles is important for physicians who prescribe these
agents.
- Language of Publication
- English
- Unique Identifier
- 95336876
- MeSH Heading (Major)
- Anti-Inflammatory Agents, Non-Steroidal|*TU; Antimalarials|*TU; Antirheumatic
Agents|AE/*TU; Arthritis, Rheumatoid|*DT; Gold|*TU
- MeSH Heading
- Clinical Trials; Cysteine|AA/TU; Drug Therapy, Combination; Human;
Methotrexate|TU; Penicillamine|TU; Sulfasalazine|TU
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1040-8711
- Country of Publication
- UNITED STATES
Record 7 from database: MEDLINE
Return To Top
- Title
- Cysteine protects Na,K-ATPase and isolated human lymphocytes from
silver toxicity.
- Author
- Hussain S; Anner RM; Anner BM
- Address
- Laboratory of Experimental Therapeutics, Geneva University Medical Center, Switzerland.
- Source
- Biochem Biophys Res Commun, 1992 Dec 30, 189:3, 1444-9
- Abstract
- Metal-binding proteins are important components of retroviruses such as human
immunodeficiency virus (HIV). Therefore, metals could be used as antiviral agents.
However, most metals are toxic for humans with the exception of silver which is toxic only
to prokaryotic cells and viruses. In addition, HIV infection causes a decrease in body cysteine.
We formed a complex of silver and cysteine, named silver-cysteine.
Healthy human lymphocytes were incubated with silver-nitrate or silver-cysteine.
Negligible cell survival was seen at 50 microM silver-nitrate. However, in presence of 1
mM cysteine, the viability remained unaffected up to 1 mM of silver.
Further, silver inhibition of isolated Na,K-ATPase was easily reversed by cysteine.
Thus, non-toxic silver-cysteine could be used as an anti-viral and cysteine-replenishing
agent.
- Language of Publication
- English
- Unique Identifier
- 93129209
- MeSH Heading (Major)
- Cysteine|*PD; Lymphocytes|CY/*DE; Na(+)-K(+)-Exchanging ATPase|AI/*ME;
Silver|*TO
- MeSH Heading
- Animal; Cell Survival|DE; Human; HIV|DE; In Vitro; Kidney Medulla|EN; Kinetics; Sheep;
Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-291X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 3.6.1.37 (Na(+)-K(+)-Exchanging ATPase); 4371-52-2 (Cysteine);
7440-22-4 (Silver)
Record 8 from database: MEDLINE
-
Return To Top
- Title
- Apoptosis in Burkitt lymphoma cells is prevented by promotion of cysteine
uptake.
- Author
- Falk MH; Meier T; Issels RD; Brielmeier M; Scheffer B; Bornkamm GW
- Address
- Institute of Clinical Molecular Biology and Tumour Genetics, GSF-National Research
Center for Environment and Health, Munich, Germany.
- Source
- Int J Cancer, 1998 Feb, 75:4, 620-5
- Abstract
- Burkitt lymphoma (BL) cells are highly sensitive to suboptimal growth conditions and
undergo apoptosis when seeded at reduced serum concentration or low cell density.
Irradiated fibroblasts can protect BL cells from apoptosis induced by lowering the serum
concentration or cell density through secretion of a survival- and proliferation-promoting
activity which is soluble and labile. Murine B cells have a restricted uptake capacity for
cystine and require cysteine for proliferation, which can be supplied
efficiently by feeder cells. Therefore, we have studied the role of cysteine
and other compounds with free thiol groups for survival and proliferation of BL cells. Cysteine,
when added alone, exerted strong toxicity on BL cells. This toxicity could be counteracted
by the addition of catalase, pyruvate or bathocuproine disulfonate (BCS), all of which
interfere with the production of hydrogen peroxide. Inhibition of the toxicity of cysteine
was necessary to unravel the survival- and growth-promoting activity of cysteine
at low cell density. Alpha-thioglycerol, beta-mercaptoethanol and dithiothreitol had
similar toxic activity in the absence of catalase, pyruvate and BCS and, through
stimulation of cysteine uptake and glutathione synthesis, displayed a
similar survival- and growth-promoting activity in the presence of the protective agents.
The survival- and proliferation-inducing activity of thiol compounds in the presence of
catalase, pyruvate and BCS was not associated with induction of BCL-2 or BAX. Cysteine/cystine
uptake and the intra/cellular glutathione level are thus important parameters, determining
the susceptibility vs. resistance of BL cells to apoptosis.
- Language of Publication
- English
- Unique Identifier
- 98126142
- MeSH Heading (Major)
- Burkitt Lymphoma|*PA; Cysteine|*ME
- MeSH Heading
- Apoptosis; B-Lymphocytes|CY; Catalase|ME; Cell Survival|DE; Glutathione|ME;
Glycerol|AA/PD; Human; Oxidation-Reduction; Phenanthrolines|PD; Proto-Oncogene
Proteins|ME; Proto-Oncogene Proteins c-bcl-2|ME; Pyruvates|ME; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0020-7136
- Country of Publication
- UNITED STATES
Record 9 from database: MEDLINE
Return To Top
- Title
- Role of the disulfide bond in Shiga toxin A-chain for toxin entry into cells.
- Author
- Garred O; Dubinina E; Polesskaya A; Olsnes S; Kozlov J; Sandvig K
- Address
- Institute for Cancer Research at The Norwegian Radium Hospital, Montebello, 0310 Oslo,
Norway.
- Source
- J Biol Chem, 1997 Apr, 272:17, 11414-9
- Abstract
- Shiga toxin consists of an enzymatically active A-chain and a pentameric binding
subunit. The A-chain has a trypsin-sensitive region, and upon cleavage two disulfide
bonded fragments, A1 and A2, are generated. To study the role of the disulfide bond, it
was eliminated by mutating cysteine 242 to serine. In T47D cells this
mutated toxin was more toxic than wild type toxin after a short incubation, whereas after
longer incubation times wild type toxin was most toxic. Cells cleaved not only wild type
but also mutated A-chain into A1 and A2 fragments. The mutated A-chain was more sensitive
than wild type toxin to Pronase, and it was degraded at a higher rate in T47D cells.
Subcellular fractionation demonstrated transport of both wild type and mutated toxin to
the Golgi apparatus. Brefeldin A, which disrupts the Golgi apparatus, protected not only
against Shiga toxin but also against the mutated toxin, indicating involvement of the
Golgi apparatus. After prebinding of Shiga(C242S) toxin to wells coated with the Shiga
toxin receptor, Gb3, trypsin treatment induced dissociation of A1 from the toxin-receptor
complex demonstrating that in addition to stabilizing the A-chain, the disulfide bond
prevents dissociation of the A1 fragment from the toxin-receptor complex.
- Language of Publication
- English
- Unique Identifier
- 97269051
- MeSH Heading (Major)
- Bacterial Toxins|*ME; Cysteine|GE/*ME; Cytotoxins|*ME; Disulfides|*ME
- MeSH Heading
- Amino Acid Sequence; Biological Transport|DE/GE; Cyclopentanes|PD; Dose-Response
Relationship, Drug; Female; Golgi Apparatus|ME; Human; Molecular Sequence Data;
Mutagenesis, Site-Directed; Point Mutation; Protein Conformation; Protein Processing,
Post-Translational; Serine|GE/ME; Support, Non-U.S. Gov't; Toxicity Tests; Tumor Cells,
Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0021-9258
- Country of Publication
- UNITED STATES
Record 10 from database: MEDLINE
Return To Top
- Title
- Bioactive organosulfur phytochemicals in Brassica oleracea vegetables--a review.
- Author
- Stoewsand GS
- Address
- Department of Food Science and Technology, New York State Agricultural Experiment
Station, Cornell University, Geneva 14456, USA.
- Source
- Food Chem Toxicol, 1995 Jun, 33:6, 537-43
- Abstract
- Sulfur-containing phytochemicals of two different kinds are present in all Brassica
oleracea (Cruciferae) vegetables (cabbage, broccoli, etc.). They are glucosinolates
(previously called thioglucosides) and S-methyl cysteine sulfoxide. These
compounds, which are derived in plant tissue by amino acid biosynthesis, show quite
different toxicological effects and appear to possess anticarcinogenic properties.
Glucosinolates have been extensively studied since the mid-nineteenth century. They are
present in plant foods besides Brassica vegetables with especially high levels in a number
of seed meals fed to livestock. About 100 different kinds of glucosinolates are known to
exist in the plant kingdom, but only about 10 are present in Brassica. The first toxic
effects of isothiocyanates and other hydrolytic products from glucosinolates that were
identified were goitre and a general inhibition of iodine uptake by the thyroid. Numerous
studies have indicated that the hydrolytic products of at least three glucosinolates,
4-methyl-sulfinylbutyl (glucoraphanin), 2-phenylethyl (gluconasturtiin) and
3-indolylmethyl (glucobrassicin), have anticarcinogenic activity. Indole-3-carbinol, a
metabolite of glucobrassicin, has shown inhibitory effects in studies of human breast and
ovarian cancers. Kale poisoning, or a severe haemolytic anaemia, was discovered in cattle
in Europe in the 1930s, but its link with the hydrolytic product of S-methyl cysteine
sulfoxide was only shown about 35 years later. S-methyl cysteine
sulfoxide and its metabolite methyl methane thiosulfinate were shown to inhibit
chemically-induced genotoxicity in mice. Thus, the cancer chemopreventive effects of
Brassica vegetables that have been shown in human and animal studies may be due to the
presence of both types of sulfur-containing phytochemicals (i.e. certain glucosinolates
and S-methyl cysteine sulfoxide).
- Language of Publication
- English
- Unique Identifier
- 95317721
- MeSH Heading (Major)
- Brassica|*CH; Cysteine|*AA/AN/PD/TO; Glucosinolates|*AN/PD/TO
- MeSH Heading
- Animal; Anticarcinogenic Agents|AN; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0278-6915
- Country of Publication
- ENGLAND
Record 11 from database: MEDLINE
- Return To Top
- Title
- Proteolytically active 2A proteinase of human rhinovirus 2 is toxic for Saccharomyces
cerevisiae but does not cleave the homologues of eIF-4 gamma in vivo or in vitro.
- Author
- Klump H; Auer H; Liebig HD; Kuechler E; Skern T
- Address
- Department of Biochemistry, Medical Faculty, University of Vienna, Austria.
- Source
- Virology, 1996 Jun, 220:1, 109-18
- Abstract
- During the replication of rhino- and enteroviruses, the translation initiation factor
elF-4 gamma is specifically cleaved by the virally encoded 2 A proteinase. This cleavage
has been proposed to lead to the inability of the host cell to translate its own capped
mRNA and to stimulate internal initiation of protein synthesis from the viral mRNA.
However, a direct causal relationship between these effects and 2A proteinase-mediated
cleavage of elF-4 gamma has remained difficult to prove, mainly because of the toxicity of
the 2A proteinase in mammalian expression systems. As an alternative approach, we placed
the cDNA sequences for the human rhinovirus 2 2A proteinase and two mutants defective in
proteolytic activity under the control of an inducible yeast Gal1-10 promoter and stably
integrated them into the yeast genome. Induction of the wildtype enzyme led to changes in
cellular morphology, an inhibition of cell division activity, and finally to cell death.
As the yeast homologues of mammalian elF-4 gamma, p150 and p130, were shown to be
refractory to cleavage by human rhinovirus 2A proteinase both in vivo and in vitro and the
rate of protein synthesis was unaffected, the toxicity of the 2A proteinase toward budding
yeast must be due to its interaction with at least one other cellular protein essential
for viability.
- Language of Publication
- English
- Unique Identifier
- 96240633
- MeSH Heading (Major)
- Cysteine Proteinases|GE/*ME/PD; Peptide Initiation Factors|*ME;
Rhinovirus|*EN; Saccharomyces cerevisiae|*DE
- MeSH Heading
- Amino Acid Sequence; Fungal Proteins|ME; Gene Expression; Human; Kinetics; Molecular
Sequence Data; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0042-6822
- Country of Publication
- UNITED STATES
Record 12 from database: MEDLINE
Return To Top
- Title
- Decreased cysteine and glutathione levels: possible determinants of
liver toxicity risk in Ghanaian subjects.
- Author
- Ankrah NA; Rikimaru T; Ekuban FA; Addae MM
- Address
- Chemical Pathology Unit, Noguchi Memorial Institute for Medical Research, University of
Ghana, Legon.
- Source
- J Int Med Res, 1994 May, 22:3, 171-6
- Abstract
- Cysteine, methionine, vitamin A, beta-carotene and glutathione (GSH)
are known to protect body tissues against oxidative damage and inflammation but their
value as protection against liver inflammation in tropical areas has received little
attention. Blood levels of these nutrients were measured in Ghanaian volunteers with
(Group 2) or without (Group 1) increased lipid peroxidation and signs of liver
inflammation, as indicated by blood malonic dialdehyde, serum alpha 1-antitrypsin and
triglyceride levels, and the alpha 1-acid glycoprotein:pre-albumin ratio. Serum levels of cysteine
and blood glutathione were significantly lower (P < 0.02) in group 2 than in group 1
volunteers. In contrast, serum levels of methionine, vitamin A and beta-carotene were
similar in both groups. Deficits in cysteine and glutathione may increase
the risk of liver toxicity from oxidants in Ghanaians.
- Language of Publication
- English
- Unique Identifier
- 94374556
- MeSH Heading (Major)
- Antioxidants|*ME; Cysteine|*BL; Glutathione|*BL; Hepatitis, Toxic|*BL
- MeSH Heading
- Adult; Aged; Biological Markers|BL; Carotene|BL; Female; Ghana; Human; Male;
Malondialdehyde|BL; Methionine|BL; Middle Age; Risk Factors; Vitamin A|BL
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-0605
- Country of Publication
- ENGLAND
Record 13 from database: MEDLINE
Return To Top
- Title
- Streptococcal pyrogenic exotoxin A, streptolysin O, exoenzymes, serotype and biotype
profiles of Streptococcus pyogenes isolates from patients with toxic shock syndrome and
other severe infections.
- Author
- Müller Alouf H; Geoffroy C; Geslin P; Bouvet A; Felten A; Günther E; Ozegowski JH;
Alouf JE
- Address
- UnitÆe des Toxines Microbiennes (URA 1858, Centre National de la Recherche
Scientifique), Institut Pasteur, Paris, France.
- Source
- Zentralbl Bakteriol, 1997 Oct, 286:3, 421-33
- Abstract
- The determination of protein M and T serotypes, biotypes and pyrogenic (erythrogenic)
exotoxin A (SPE A), streptolysin O (SLO), streptokinase (SK), hyaluronidase (HA) and cysteine
proteinase release by 212 S. pyogenes isolates from patients with severe invasive group A
streptococcal (GAS) infections, among them 74 cases of streptococcal toxic shock syndrome
(STSS) has been investigated. M1 or M3 serotypes were expressed by 25% of the isolates
(53/212), whereas 59% (125/212) belonged to 15 other different serotypes and 16% (34/212)
were untypeable. Of the 74 isolates from STSS patients, 42% (31/74) expressed M1 and to a
lesser extent M3 serotypes versus 19% of the non STSS isolates (26/138). Among the ten
different biotypes known, biotypes 1 and 3 were prevalent, particularly the former in the
case of STSS isolates. SPE A was detectably produced by about 25% (54/212) of the strains.
However, as high as 40.5% of the STSS isolates (30/74) versus 17.4% of non STSS isolates
(24/138) released SPE A. Moreover, 67% of the SPE A producing strains were of serotype M1
or M3. SK and HA were released by 71% and 10% of the isolates respectively. All strains
released SLO (4 to 256 HU/ml) and 85% cysteine proteinase. No
relationship between toxin or enzyme titer and the type of disease or clinical origin of
the strains was found. Culture supernatants of all isolates showed moderate to high
lymphocyte transforming activity with index values ranging from 14.5 to 50.3 including
those strains which did not release detectable amounts of SPE A suggesting that SPE C and
other mitogenic factor(s) are released by the isolates investigated.
- Language of Publication
- English
- Unique Identifier
- 98027322
- MeSH Heading (Major)
- Shock, Septic|EP/*MI; Streptococcal Infections|EP/*MI; Streptococcus pyogenes|CL/IM/*ME
- MeSH Heading
- Adolescence; Adult; Aged; Bacterial Proteins|AN/IM/ME; Bacterial Typing Techniques;
Child; Child, Preschool; Culture Media, Conditioned|PD; Cysteine
Proteinases|AN/ME; Exotoxins|AN/IM/ME; Female; Human; Hyaluronoglucosaminidase|AN/ME;
Infant; Lymphocyte Transformation; Male; Middle Age; Serotyping; Streptokinase|AN/ME;
Streptolysins|AN/ME
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0934-8840
- Country of Publication
- GERMANY
Record 14 from database: MEDLINE
Return To Top
- Title
- Biotransformation of trichloroethene: dose-dependent excretion of
2,2,2-trichloro-metabolites and mercapturic acids in rats and humans after inhalation.
- Author
- Bernauer U; Birner G; Dekant W; Henschler D
- Address
- Institut fÂur Toxikologie, UniversitÂat WÂurzburg, Germany.
- Source
- Arch Toxicol, 1996, 70:6, 338-46
- Abstract
- Chronic bioassays with trichloroethene (TRI) demonstrated carcinogenicity in mice
(hepatocellular carcinomas) and rats (renal tubular cell adenomas and carcinomas). The
chronic toxicity and carcinogenicity is due to bioactivation reactions. TRI is metabolized
by cytochrome P450 and by conjugation with glutathione. Glutathione conjugation results in
S-(dichlorovinyl) glutathione (DCVG) and is presumed to be the initial biotransformation
step resulting in the formation of nephrotoxic metabolites. Enzymes of the mercapturic
acid pathway cleave DCVG to the corresponding cysteine S-conjugate, which
is, after translocation to the kidney, cleaved by renal cysteine
S-conjugate beta -lyase to the electrophile chlorothioketene. After N-acetylation, cysteine
S-conjugates are also excreted as mercapturic acids in urine. The object of this study was
the dose-dependent quantification of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine,
trichloroethanol and trichloroacetic acid, as markers for the glutathione- and cytochrome
P450-mediated metabolism, respectively, in the urine of humans and rats after exposure to
TRI. Three male volunteers and four rats were exposed to 40, 80 and 160 ppm TRI for 6 h. A
dose-dependent increase in the excretion of trichloroacetic acid, trichloroethanol and
N-acetyl-S-(dichlorovinyl)-L-cysteine after exposure to TRI was found
both in humans and rats. Amounts of 3100 mumol trichloroacetic acid + trichloroethanol and
0.45 mumol mercapturic acids were excreted in urine of humans over 48 h after exposure to
160 ppm TRI. The ratio of trichloroacetic acid + trichloroethanol/mercapturic acid
excretion was comparable in rats and humans. A slow rate of elimination with urine of
N-acetyl-S-(dichlorovinyl)-L-cysteine was observed both in humans and in
rats. However, the ratio of the two isomers of N-acetyl-S-(dichlorovinyl)-L-cysteine
was different in man and rat. The results confirm the finding of the urinary excretion of
mercapturic acids in humans after TRI exposure and suggest the formation of reactive
intermediates in the metabolism of TRI after bioactivation by glutathione also in humans.
- Language of Publication
- English
- Unique Identifier
- 96253326
- MeSH Heading (Major)
- Acetylcysteine|*UR; Trichloroethylene|AD/*ME/*PK
- MeSH Heading
- Administration, Inhalation; Adult; Aged; Animal; Biotransformation; Cysteine|AA/UR;
Dose-Response Relationship, Drug; Female; Glutathione|ME; Human; Male; Mass
Fragmentography; Middle Age; Rats; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0340-5761
- Country of Publication
- GERMANY
Record 15 from database: MEDLINE
Return To Top
- Title
- Inhibition of the conversion of pre-interleukins-1 alpha and 1 beta to mature cytokines
by p-benzoquinone, a metabolite of benzene.
- Author
- Niculescu R; Bradford HN; Colman RW; Kalf GF
- Address
- Department of Biochemistry and Molecular Biology, Jefferson Medical College, Thomas
Jefferson University, Philadelphia, PA 19107, USA.
- Source
- Chem Biol Interact, 1995 Dec, 98:3, 211-22
- Abstract
- Chronic exposure of humans to benzene causes severe bone marrow cell depression leading
to aplastic anemia. Marrow stromal macrophage dysfunction and deficient interleukin-1
production has been reported for patients with severe aplastic anemia. The stromal
macrophage, a target of benzene toxicity, is involved in hematopoietic regulation through
the synthesis of several cytokines including interleukin-1, which is required for
production by stromal fibroblasts of a number of cytokines required for the survival of
hematopoietic progenitor cells. We have previously demonstrated that hydroquinone, a major
toxic metabolite of benzene in marrow, prevents the proteolytic conversion of 31 kDa
pre-interleukin-1 alpha to the 17 kDa cytokine by calpain in purified murine stromal
macrophages. Furthermore, stromal macrophages from benzene-treated mice produce the 31 kDa
pre-interleukin-1 alpha when stimulated in culture with endotoxin, but cannot convert the
precursor to interleukin-1 alpha. In this report, we show that 1,4-benzoquinone, the
oxidation product of hydroquinone in the cell, causes a concentration-dependent inhibition
of highly purified human platelet calpain with an IC50 of 3 microM. Hydroquinone also
inhibits the processing of pre-interleukin-1 beta by interleukin-1 beta convertase. The
addition of 2 microM hydroquinone to B1 cells that undergo autocrine stimulation by
interleukin-1 beta resulted in the cessation of autocrine cell growth and interleukin-1
beta secretion into the culture medium, as determined by Western immunoblots of the
culture supernatants. Purified converting enzyme treated with 3 microM benzoquinone was
incapable of converting 31 kDa recombinant pre-interleukin-1 beta to the 17 kDa mature
cytokine as analyzed by polyacrylamide gel electrophoresis and Western immunoblotting.
These findings support our observations in a mouse model that benzene-induced bone marrow
cell depression results from a lack of interleukin-1 alpha subsequent to an inhibition by
benzoquinone of calpain, the protease required for converting pre-interleukin-1 alpha to
active cytokine. The results may provide a basis for studying benzene-induced aplastic
anemia in a mouse model.
- Language of Publication
- English
- Unique Identifier
- 96135283
- MeSH Heading (Major)
- Benzoquinones|*TO; Calpain|*AI; Cysteine Proteinases|*ME;
Interleukin-1|*ME; Protein Precursors|*ME
- MeSH Heading
- Benzene|ME/TO; Blotting, Western; Cell Division|DE; Cysteine Proteinase
Inhibitors|TO; Human; Hydroquinones|TO; Indomethacin|TO; Macrophages|DE/ME; Recombinant
Proteins|ME; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.; Tumor Cells,
Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0009-2797
- Country of Publication
- IRELAND
Record 16 from database: MEDLINE
-
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- Title
- Excretion of N-acetyl-S-(1-phenyl-2-hydroxyethyl)-cysteine and
N-acetyl-S-(2-phenyl-2-hydroxyethyl)-cysteine in workers exposed to
styrene.
- Author
- Maestri L; Imbriani M; Ghittori S; Capodaglio E; Gobba F; Cavalleri A
- Address
- Fondazione Salvatore Maugeri I.R.C.C.S., Pavia, Italy.
- Source
- Sci Total Environ, 1997 Jun, 199:1-2, 13-22
- Abstract
- Styrene (S) has been shown to be responsible for neurotoxic effects, including
behavioural changes and neuroendocrine disturbances. The initial step of S metabolism is
conversion to styrene 7,8-epoxide (SO), which is present in two enantiomeric forms
[(R)(+)-SO and (S)(-)-SO]; this electrophilic intermediate is considered to be directly
responsible for most toxic effects of S. The major urinary metabolites derived from the
biotransformation of SO in man are mandelic acid (MA) and phenylglyoxylic acid (PGA). In
rats an alternative pathway has been demonstrated, which involves the conjugation of SO to
glutathione (GSH), leading to the excretion of two specific mercapturic acids,
N-acetyl-S-(-(1-phenyl-2-hydroxyethyl)-cysteine [M1] and
N-acetyl-S-(2-phenyl-2-hydroxy-ethyl)-cysteine [M2]; a close relationship
has been found between exposure to S and urinary excretion of M1 and M2 in rats. As a
consequence of the chiral nature of SO, both M1 and M2 consist of two diastereoisomers
(M1-'R', M1-'S', M2-'R' and M2-'S'). Early reports have shown that the conversion of S to
mercapturic acids is much lower in man (below 1% of the absorbed dose) than in rats (about
10%). We propose an analytical method for the determination of urinary M1 and M2 in man,
which involves a urine clean-up by a chromatographic technique with a short reversed-phase
pre-column; purified samples are then deacetylated with porcine acylase and deproteinized
by centrifugal ultrafiltration. A derivatization is then performed with o-phthaldialdehyde
and 2-mercaptoethanol and the fluorescent derivatives are separated on a reversed-phase
analytical column. The mobile phase consists of acetate buffer and methanol mixed at
variable proportions, the fluorescence detector is set at 330 nm (exc.) and 440 nm (em.).
M1-'S' and M1-'R' are separated (retention times = 52.8 and 73.7 min, respectively) while
the diastereoisomers of M2 coelute as a single peak at 70.5 min. The detection limit is
about 7 micrograms/l, the coefficients of variation are below 7% and the error percentages
are less than 6%. The method was applied to 25 urine samples from workers exposed to S:
significant correlations were found between mercapturic acids and MA and PGA, the best
correlation being between M2 and PGA (r = 0.79). Urine samples form unexposed subjects
showed no detectable amounts of the analytes. A high stereoselectivity is shown by the
enzymes involved in the metabolism of S to mercapturic acids: M1-'S', which derives from
(S)-SO, is excreted in much higher amounts than M1-'R', which derives from (R)-SO.
- Language of Publication
- English
- Unique Identifier
- 97344396
- MeSH Heading (Major)
- Acetylcysteine|*AA/UR; Occupational Exposure|*; Styrenes|*AE/CH/UR
- MeSH Heading
- o-Phthalaldehyde|CH; Animal; Binding Sites; Biotransformation; Carcinogens|ME;
Chromatography, High Pressure Liquid; Cysteine|AA/UR; Environmental
Monitoring; Epoxy Compounds|UR; Glutathione|UR; Glyoxylates|UR; Human; Male; Mandelic
Acids|UR; Mercaptoethanol|CH; Rats; Reference Standards; Spectrometry, Fluorescence;
Stereoisomerism; Ultrafiltration
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0048-9697
- Country of Publication
- NETHERLANDS
Record 17 from database: MEDLINE
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- Title
- Poliovirus 2Apro expression inhibits growth of yeast cells.
- Author
- Barco A; Carrasco L
- Address
- Centro de Biologia Molecular (CSIC-UAM), Universidad AutÆonoma de Madrid, Canto Blanco,
Spain.
- Source
- FEBS Lett, 1995 Aug, 371:1, 4-8
- Abstract
- Poliovirus encodes two proteases, 2Apro and 3Cpro that participate in the processing of
the viral polyprotein and cleave a number of host proteins. Both proteases have been
cloned and expressed in an inducible manner in Saccharomyces cerevisiae cells. The
expression of 2Apro, but not 3Cpro, was highly toxic for yeast cells such that growth was
arrested after 5 h of induction and cell survival sharply declined. Cellular morphology
was profoundly modified by expression of poliovirus 2Apro, in such a way that electron
dense granules and autophagosomic bodies arise in the cytoplasm. Experiments aimed at
defining the yeast function affected by 2Apro suggested that translation was not the
target of protease toxicity, but showed that RNA synthesis was profoundly blocked.
- Language of Publication
- English
- Unique Identifier
- 95394144
- MeSH Heading (Major)
- Cysteine Proteinases|*BI/GE/PH; Polioviruses, Human 1-3|*EN;
Saccharomyces cerevisiae|*GD/GE/ME
- MeSH Heading
- DNA, Fungal|BI; Fungal Proteins|BI; Galactose; Glucose; Hela Cells; Human; RNA,
Fungal|BI; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-5793
- Country of Publication
- NETHERLANDS
Record 18 from database: MEDLINE
- Return To Top
- Title
- Expression and characterization of group A Streptococcus extracellular cysteine
protease recombinant mutant proteins and documentation of seroconversion during human
invasive disease episodes.
- Author
- Gubba S; Low DE; Musser JM
- Address
- Institute for the Study of Human Bacterial Pathogenesis, Department of Pathology, Baylor
College of Medicine, Houston, Texas 77030, USA.
- Source
- Infect Immun, 1998 Feb, 66:2, 765-70
- Abstract
- A recent study with isogenic strains constructed by recombinant DNA strategies
unambiguously documented that a highly conserved extracellular cysteine
protease expressed by Streptococcus pyogenes (group A Streptococcus [GAS]) is a critical
virulence factor in a mouse model of invasive disease (S. Lukomski, S. Sreevatsan, C.
Amberg, W. Reichardt, M. Woischnik, A. Podbielski, and J. M. Musser, J. Clin. Invest.
99:2574-2580, 1997). To facilitate further investigations of the streptococcal cysteine
protease, recombinant proteins composed of a 40-kDa zymogen containing a C192S amino acid
substitution that ablates enzymatic activity, a 28-kDa mature protein with the C192S
replacement, and a 12-kDa propeptide were purified from Escherichia coli containing His
tag expression vectors. The recombinant C192S zymogen retained apparently normal
structural integrity, as assessed by the ability of purified wild-type streptococcal cysteine
protease to process the 40-kDa molecule to the 28-kDa mature form. All three recombinant
purified proteins retained immunologic reactivity with polyclonal and monoclonal
antibodies. Humans with a diverse range of invasive disease episodes (erysipelas,
cellulitis, pneumonia, bacteremia, septic arthritis, streptococcal toxic shock syndrome,
and necrotizing fasciitis) caused by six distinct M types of GAS seroconverted to the
streptococcal cysteine protease. These results demonstrate that this GAS
protein is expressed in vivo during the course of human infections and thereby provide
additional evidence that the cysteine protease participates in
host-pathogen interactions in some patients.
- Language of Publication
- English
- Unique Identifier
- 98114384
- MeSH Heading (Major)
- Cysteine Proteinases|*BI/IM; Recombinant Proteins|*BI; Streptococcal
Infections|*EN; Streptococcus pyogenes|*EN
- MeSH Heading
- Animal; Enzyme Precursors|ME; Human; Molecular Weight; Mutation; Rabbits; Support,
Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0019-9567
- Country of Publication
- UNITED STATES
Record 19 from database: MEDLINE
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- Title
- Depletion of total cysteine, glutathione, and homocysteine
in plasma by ifosfamide/mesna therapy.
- Author
- Lauterburg BH; Nguyen T; Hartmann B; Junker E; Küpfer A; Cerny T
- Address
- Department of Clinical Pharmacology, University of Bern, Switzerland.
- Source
- Cancer Chemother Pharmacol, 1994, 35:2, 132-6
- Abstract
- The sulfhydryl status of cells, particularly the intracellular concentration of
glutathione, is a critical determinant of the response of tumor and normal cells to
cytostatic drugs. Recent data indicate that the administration of mercaptoethane sulfonate
(mesna), which is often combined with ifosfamide, markedly decreases the circulating
concentration of total cysteine and could thereby influence the response
of the organism to the cytotoxic effects of chemotherapy. The aim of the present study was
to assess the effects of the combination of ifosfamide/mesna on sulfhydryl and disulfide
homeostasis in tumor patients. Ifosfamide was infused into 14 patients with advanced
sarcoma for 5 days at a dose of 2.4-3.2 g/m2 per day together with mesna. The plasma
concentrations of total mesna, cysteine, glutathione, and homocysteine
were measured before and on days 1 and 6 of the first course of ifosfamide/mesna therapy
and prior to the next course of chemotherapy, and the urinary excretion of cysteine
and mesna was monitored daily using a high-performance liquid chromatography (HPLC)
method. Ifosfamide/mesna resulted in a marked depletion of circulating total cysteine,
i.e., cysteine, cystine, and cysteine mixed disulfides
[from 245 +/- 36 to 50 +/- 14 nmol/ml (mean +/- 95% CI) on day 6], total glutathione (from
6.9 +/- 1.1 to 2.5 +/- 1.1 nmol/ml), and total homocysteine (from 12.3 +/- 2.1 to 1.4 +/-
1.1 nmol/ml). The values returned to baseline levels prior to the next course of
chemotherapy. The urinary excretion of cysteine increased significantly
from 0.28 to 1.82 mmol/day on the 1st day, whereupon it returned toward baseline. An
average of 62% +/- 6% of the delivered dose of mesna was recovered in urine. The
combination of ifosfamide/mesna results in depletion of circulating total cysteine,
glutathione, and homocysteine. This marked derangement of sulfhydryl and disulfide
homeostasis could modulate the efficacy and toxicity of ifosfamide/mesna therapy.
- Language of Publication
- English
- Unique Identifier
- 95079579
- MeSH Heading (Major)
- Antineoplastic Agents, Combined|*TU; Cysteine|*BL/UR; Glutathione|*BL;
Homocysteine|*BL; Sarcoma|BL/*DT
- MeSH Heading
- Adult; Aged; Chromatography, High Pressure Liquid; Female; Homeostasis|DE; Human;
Ifosfamide|TU; Infusions, Intravenous; Male; Mesna|BL/TU; Middle Age; Support, Non-U.S.
Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0344-5704
- Country of Publication
- GERMANY
Record 20 from database: MEDLINE
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- Title
- CPP32 inhibition prevents Fas-induced ceramide generation and apoptosis in human cells.
- Author
- Gamen S; Marzo I; Anel A; Piñeiro A; Naval J
- Address
- Departamento de BioquÆimica y Biologia Molecular y Celular, Facultad de Ciencias,
Universidad de Zaragoza, Spain.
- Source
- FEBS Lett, 1996 Jul, 390:2, 232-7
- Abstract
- Intracellular activation of sphingomyelinase, leading to ceramide generation, and
ICE-like proteases have been implicated in TNF and Fas-induced apoptosis, but the links
between these intracellular apoptotic mediators remain undefined. We show here that a
specific peptide inhibitor of the ICE-like protease CPP32/Yama (DEVD-CHO) blocks
anti-Fas-induced apoptosis in Jurkat and U937 cells, while having no effect on TNF-induced
apoptosis in U937 cells. This peptide also prevents ceramide accumulation induced by Fas
engagement. Jurkat and U937 cells, as well as their mtDNA-depleted derived lines (rho
degree cells), were sensitive to ceramide toxicity, which was not prevented by ICE-like
protease inhibitors. These results, taken together, suggest that ICE-like protease
activation is a prerequisite for ceramide generation and subsequent apoptosis, at least in
the case of Fas-induced cell death.
- Language of Publication
- English
- Unique Identifier
- 96305811
- MeSH Heading (Major)
- Antigens, CD95|*ME; Apoptosis|*DE/PH; Ceramides|*BI; Cysteine
Proteinase Inhibitors|CH/*PD; Cysteine Proteinases|*ME
- MeSH Heading
- Amino Acid Chloromethyl Ketones|CH/PD; Amino Acid Sequence; Cell Line; DNA,
Mitochondrial|ME; Human; Molecular Sequence Data; Oligopeptides|CH/PD; Support, Non-U.S.
Gov't; Tumor Necrosis Factor|ME
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-5793
- Country of Publication
- NETHERLANDS
Record 21 from database: MEDLINE
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- Title
- Modulation of radiation-induced apoptosis by thiolamines.
- Author
- Warters RL; Roberts JC; Wilmore BH; Kelley LL
- Address
- Department of Radiation Oncology, University of Utah Health Sciences Center, Salt Lake
City 84132, USA.
- Source
- Int J Radiat Biol, 1997 Oct, 72:4, 439-48
- Abstract
- Exposure to the thiolamine radioprotector N-(2-mercaptoethyl)-1,3-propanediamine
(WR-1065) induced apoptosis in the mouse TB8.3 hybridoma after a 60-min (LD50 = 4.5 mM) or
during a 20-h (LD50 = 0.15 mM) exposure. In contrast, a 20-h exposure to 17 mM L-cysteine
or 10 mM cysteamine was required to induce 50% apoptosis within 20 h. Apoptosis was not
induced by either a 60-min or 20-h exposure to 10 mM of the thiazolidine prodrugs ribose-cysteine
(RibCys) or ribose-cysteamine (RibCyst). Thiolamine-induced apoptosis appeared to be a
p53-independent process since it was induced by WR-1065 exposure in human HL60 cells.
Exposure to WR-1065 (4 mM for 15 min) or cysteine (10 mM for 60 min)
before and during irradiation protected cells against the induction of both DNA
double-strand breaks and apoptosis, while exposure to RibCys (10 mM for 3 h) did not.
Treatment with either WR-1065, cysteine, RibCys or RibCyst for 60 min
beginning 60 min after irradiation did not affect the level of radiation-induced
apoptosis. In contrast, treatment with either cysteine, cysteamine or
RibCys for 20 h beginning 60 min after irradiation enhanced radiation-induced apoptosis.
Similar experiments could not be conducted with WR-1065 because of its extreme toxicity.
Our results indicate that thiolamine enhancement of radiation-induced apoptosis is not
involved in their previously reported capacity to reduce radiation-induced mutations.
- Language of Publication
- English
- Unique Identifier
- 98002626
- MeSH Heading (Major)
- Apoptosis|*DE/*RE; Cysteamine|AA/*PD; Cysteine|AA/*PD;
Mercaptoethylamines|*PD; Prodrugs|*PD; Radiation-Protective Agents|*PD
- MeSH Heading
- Animal; Human; Hybridomas; HL-60 Cells|CY/DE/RE; Mice; Support, U.S. Gov't, Non-P.H.S.;
Support, U.S. Gov't, P.H.S.; T-Lymphocytes|CY/DE/ME
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0955-3002
- Country of Publication
- ENGLAND
Record 22 from database: MEDLINE
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- Title
- The role of glutathione conjugation in the development of kidney tumours in rats exposed
to trichloroethylene.
- Author
- Green T; Dow J; Ellis MK; Foster JR; Odum J
- Address
- Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
- Source
- Chem Biol Interact, 1997 Jul, 105:2, 99-117
- Abstract
- Trichloroethylene is metabolised to a very minor extent (< 0.01% of the dose) by
conjugation with glutathione, a metabolic pathway which leads to the formation of
S-(1,2-dichlorovinyl)-L-cysteine (DCVC), a bacterial mutagen and
nephrotoxin activated by the renal enzyme beta-lyase. The role of this metabolic pathway
in the development of the nephrotoxicity and subsequent tumour formation seen in rats
exposed to trichloroethylene has been evaluated. The pathway has been assessed
quantitatively in vivo in rats, and in rats, mice and humans in vitro. Trichloroethylene
was found to be a very weak nephrotoxin. There was no evidence of morphological change in
the kidneys and only small increases in biochemical markers of kidney damage in rats dosed
with 2000 mg/kg trichloroethylene by gavage for 42 days. N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine
was detected in the urine of rats dosed with 500 and 2000 mg/kg trichloroethylene for up
to 10 days at levels equivalent to 0.001-0.008% of the dose. In vitro, the rate of
conjugation of trichloroethylene with glutathione in the liver was higher in the mouse,
2.5 pmol/min per mg protein, than the rat, 1.6 pmol/min per mg protein, and in human liver
the rates were extremely low, 0.02-0.37 pmol/min per mg protein. Comparisons of the
metabolism of DCVC by renal beta-lyase and N-acetyl transferase showed that metabolism by
N-acetyl transferase was two orders of magnitude greater than that by beta-lyase and that
beta-lyase activity in rat kidney was 11-fold greater than that in human kidney. When the
nephrotoxicity of DCVC was compared in rats and mice, the mouse was found to be 5-10 fold
more sensitive than the rat. The no effect level in the rat was 10 mg/kg, a dose which is
three orders of magnitude higher than the amount of DCVC formed from trichloroethylene in
vivo. The lack of correlation between metabolism by this pathway and the rat specific
tumours, together with questions concerning the potency of DCVC at the levels formed from
trichloroethylene, suggests that DCVC may not be involved in the renal toxicity and
subsequent tumour development seen in rats and that further evaluation of the mechanism(s)
involved in the nephrotoxic response is warranted.
- Language of Publication
- English
- Unique Identifier
- 97395585
- MeSH Heading (Major)
- Glutathione|AA/*ME; Kidney Neoplasms|*CI/ME; Trichloroethylene|ME/*TO
- MeSH Heading
- Animal; Arylamine N-Acetyltransferase|ME; Chromatography, High Pressure Liquid; Cysteine|AA/ME;
Human; In Vitro; Isomerism; Kidney|EN; Kinetics; Lyases|ME; Male; Mice; Rats; Rats, Inbred
F344; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0009-2797
- Country of Publication
- IRELAND
Record 23 from database: MEDLINE
-
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- Title
- Processing/activation of at least four interleukin-1beta converting enzyme-like
proteases occurs during the execution phase of apoptosis in human monocytic tumor cells.
- Author
- MacFarlane M; Cain K; Sun XM; Alnemri ES; Cohen GM
- Address
- Centre for Mechanisms of Human Toxicity, University of Leicester, United Kingdom.
- Source
- J Cell Biol, 1997 Apr, 137:2, 469-79
- Abstract
- Identification of the processing/activation of multiple interleukin-1beta converting
enzyme (ICE)-like proteases and their target substrates in the intact cell is critical to
our understanding of the apoptotic process. In this study we demonstrate
processing/activation of at least four ICE-like proteases during the execution phase of
apoptosis in human monocytic tumor THP.1 cells. Apoptosis was accompanied by processing of
Ich-1, CPP32, and Mch3alpha to their catalytically active subunits, and lysates from these
cells displayed a proteolytic activity with kinetics, characteristic of CPP32/Mch3alpha
but not of ICE. Fluorescence-activated cell sorting was used to obtain pure populations of
normal and apoptotic cells. In apoptotic cells, extensive cleavage of Ich-1, CPP32, and
Mch3alpha. was observed together with proteolysis of the ICE-like protease substrates,
poly (ADP-ribose) polymerase (PARP), the 70-kD protein component of U1 small nuclear
ribonucleoprotein (U1-70K), and lamins A/B. In contrast, no cleavage of CPP32, Mch3alpha
or the substrates was observed in normal cells. In cells exposed to an apoptotic stimulus,
some processing of Ich-1 was detected in morphologically normal cells, suggesting that
cleavage of Ich-1 may occur early in the apoptotic process. The ICE-like protease
inhibitor, benzyloxycarbonyl-Val-Ala-Asp (OMe) fluoromethyl ketone (Z-VAD.FMK), inhibited
apoptosis and cleavage of Ich-1, CPP32, Mch3alpha, Mch2alpha, PARP, U1-70K, and lamins.
These results suggest that Z-VAD.FMK inhibits apoptosis by inhibiting a key effector
protease upstream of Ich-1, CPP32, Mch3alpha, and Mch2alpha. Together these observations
demonstrate that processing/activation of Ich-1, CPP32, Mch3alpha, and Mch2alpha
accompanies the execution phase of apoptosis in THP.1 cells. This is the first
demonstration of the activation of at least four ICE-like proteases in apoptotic cells,
providing further evidence for a requirement for the activation of multiple ICE-like
proteases during apoptosis.
- Language of Publication
- English
- Unique Identifier
- 97274108
- MeSH Heading (Major)
- Apoptosis|DE/*PH; Cysteine Proteinases|*ME; Monocytes|*CY/EN
- MeSH Heading
- Cysteine Proteinase Inhibitors|PD; Enzyme Activation; Human; Kinetics;
Nuclear Proteins|ME; NAD+ ADP-Ribosyltransferase|ME; Protein Precursors|ME;
Ribonucleoproteins, Small, U1|ME; Support, U.S. Gov't, P.H.S.; Tumor Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0021-9525
- Country of Publication
- UNITED STATES
Record 24 from database: MEDLINE
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- Title
- The function of gamma-glutamyl transpeptidase as a determinant in cell sensitivity to
azaserine toxicity.
- Author
- Perantoni A; Rice JM; Nardone RM; Berman JJ; Curphey TJ
- Address
-
- Source
- Chem Biol Interact, 1984 Nov, 52:1, 39-50
- Abstract
- The enzyme gamma-glutamyl transpeptidase (GGT) is characteristically present at high
levels in mammalian cells that are vulnerable in vivo to the selectively toxic and
carcinogenic effects of the naturally occurring diazo amino acid L-azaserine. The possible
role of GGT as a determinant of cellular sensitivity to azaserine toxicity was
investigated. No correlation was found between GGT activity and the abilities of different
cell lines or GGT-deficient cell strains of TuWi, a human nephroblastoma-derived line high
in GGT, to accumulate azaserine. However, the thiols glutathione and cysteine
were found to inhibit the toxicity of azaserine in cultures of TuWi. In addition, maleate
lowered both intracellular and extracellular glutathione levels and enhanced sensitivity
of TuWi cells to azaserine, while serine-borate, a potent inhibitor of GGT, increased
extracellular glutathione levels and inhibited azaserine toxicity. Since extracellular
glutathione accumulation, which may reflect the rate of cellular glutathione turnover, is
increased in cultures of azaserine-resistant, GGT-deficient strains of TuWi, we propose
that GGT enhances cellular sensitivity to azaserine primarily by increasing the rate of
glutathione turnover, thus removing the glutathione from detoxification pathways.
- Language of Publication
- English
- Unique Identifier
- 85049180
- MeSH Heading (Major)
- gamma-Glutamyltransferase|*ME; Azaserine|*TO
- MeSH Heading
- Animal; Cell Line; Cell Survival|DE; Cricetulus; Cysteine|PD;
Glutathione|AA/PD; Hamsters; Human; Kidney Neoplasms; Kinetics; Liver|EN; Lung; Male;
Nephroblastoma; Rats; Rats, Inbred F344|RATS INBRED F 344
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0009-2797
- Country of Publication
- NETHERLANDS
- CAS Registry/EC Number
- EC 2.3.2.2 (gamma-Glutamyltransferase); 115-02-6 (Azaserine); 27025-41-8 (glutathione
disulfide); 4371-52-2 (Cysteine); 70-18-8 (Glutathione)
Record 25 from database: MEDLINE
Reference in Article By Karl Loren
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- Title
- Collagenase inhibitors: rationale for their use in treating corneal ulceration.
- Author
- Berman
- Address
-
- Source
- Int Ophthalmol Clin, 1975 Winter, 15:4, 49-66
- Abstract
- Tissue collagenases have been implicated in corneal ulceration in human corneal disease
and in ulceration of the rabbit cornea that has served as a model system. Such enzymes
from the rabbit and human cornea are inhibited by metal-binding agents of the EDTA type,
by thiols, and by the human serum antiprotease alpha2-macroglobulin. Determination of the
relative efficacies of collagenase inhibitors indicates that EDTA and Ca-EDTA are about
one hundred times more effective on a molar basis than L-cysteine and its
derivatives, N-acetyl-L-cysteine and D-penicillamine. The
alpha2-macroglobulin on a molar basis, is superior as an inhibitor to the metal-binding
agents and thiols. Although Ca may be a necessary cofactor of the corneal collagenases,
such a requirement has not been established unequivocally. Inhibition and isotope studies
do indicate a requirement for Zn. Thiols are thought to inhibit corneal collagenases by
binding to or removing an intrinsic metal cofactor (Zn), and/or possibly by reducing one
or more disulfide bonds. Inhibition by both EDTA-type agents and thiols is largely
reversible by dialysis. The human alpha2-macroglobulin appears to inhibit corneal
colleagenases irreversibly by forming tight complexes with them. Ca-EDTA, cysteine,
and acetylcysteine, given as eyedrops, are able to prevent or retard ulceration in the
alkali-burned rabbit cornea. They appear to have some efficacy in the prevention of
corneal ulceration in humans. EDTA-type compounds are quite stable under routine storage,
while acetylcysteine is more stable than cysteine.
EDTA is quite toxic and should not be used as eye medication. Ca-EDTA has a low toxicity,
and cysteine and acetylcysteine have even lower toxicity. It is not yet
certain which inhibitor has the most favorable therapeutic index for clinical use, or is
the optimal mode of drug delivery known. However, the collagenase inhibitors seem to have
therapeutic promise in the prevention of corneal ulceration.
- Language of Publication
- English
- Unique Identifier
- 76189571
- MeSH Heading (Major)
- Corneal Ulcer|*DT; Microbial Collagenase|*AI/ME
- MeSH Heading
- alpha 1-Antitrypsin|TU; alpha-Macroglobulins|TU; Acetylcysteine|AE/TU; Animal;
Calcium|AE/ME/TU; Cyclic AMP|PH; Cysteine|AE/ME/TU; Disease Models,
Animal; Edetic Acid|AE/ME/TU; Human; Peptide Hydrolases|AI; Steroids|PH; Tropocollagen;
Zinc Radioisotopes
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0020-8167
- Country of Publication
- UNITED STATES
Record 26 from database: MEDLINE
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- Title
- Apoptosis and necrosis in toxicology: a continuum or distinct modes of cell death?
- Author
- Raffray M; Cohen GM
- Address
- MRC Toxicology Unit, University of Leicester, UK.
- Source
- Pharmacol Ther, 1997 Sep, 75:3, 153-77
- Abstract
- Mounting evidence indicates that apoptosis rather than necrosis predominates in many
cytolethal toxic injuries. Associated cell death models of apoptosis and necrosis are
either: (1) totally separate death modes, (2) a continuum whereby they are extremes of
biochemically overlapping death pathways, or (3) essentially distinct processes with only
limited molecular and cell biology overlap. We conclude that the current balance of
evidence favours the third of these options. The established axiom that, even when
considering the same toxicant, injury amplitude (dose) is a primary determinant of whether
cells die via active cell death (apoptosis) or failure of homeostasis (necrosis) remains
valid. Tissue selectivity of toxicants can stem from the apoptotic or necrotic thresholds
at which different cells die, as well as targeting factors such as toxicokinetics,
receptor recognition, bioactivation, and cell-specific lesions.
- Language of Publication
- English
- Unique Identifier
- 98164895
- MeSH Heading (Major)
- Apoptosis|DE/GE/*PH; Necrosis|*; Toxicology|*
- MeSH Heading
- Animal; Cell Membrane Permeability; Cysteine Proteinases|ME;
Cytoskeleton; DNA Fragmentation; Gene Expression Regulation|PH; Human; Hydrogen-Ion
Concentration; Ion Transport; Mitochondria|EN; Models, Biological; Reactive Oxygen Species
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0163-7258
- Country of Publication
- ENGLAND
Record 27 from database: MEDLINE
-
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- Title
- No-induced oxidative stress and glutathione metabolism in rodent and human cells.
- Author
- Luperchio S; Tamir S; Tannenbaum SR
- Address
- Massachusetts Institute of Technology, Division of Toxicology, Cambridge 02139-4307,
USA.
- Source
- Free Radic Biol Med, 1996, 21:4, 513-9
- Abstract
- Nitric oxide (NO.), a radical species produced by many types of cells, is known to play
a critical role in both regulatory processes and cell defense, yet it may also participate
in collateral reactions, leading to DNA damage and cell death in both NO-generating and
neighboring cells. Glutathione has been shown to protect cells from the toxic effects of
free radicals and reactive oxygen species. The goal of this study was to investigate
whether differences in glutathione metabolism could account for the resistance or
sensitivity to cell killing by NO.. The cytotoxic effect of NO. was examined in CHO-AA8
(Chinese Hamster Ovary) cells and TK6 (human lymphoblastoid) cells pretreated with
L-buthionine SR-sulfoximine (BSO), a potent inhibitor of gamma-glutamylcysteine
synthetase, and with 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), an irreversible
inhibitor of glutathione reductase. The consequences resulting from the depletion of
glutathione levels and from the arrest of oxidoreduction allowed us to show the
involvement of glutathione in protecting cells from NO. and to investigate the importance
of changes in glutathione metabolism on NO-induced toxicity. In CHO-AA8 cells, we found
that treatment with NO. resulted in the oxidation of reduced glutathione (GSH) to oxidized
glutathione (GSSG) and to mixed glutathione disulfides (GSSR). The resulting depletion of
GSH stimulated its de novo synthesis, enabling the cells to resist killing by NO.. A
slight difference in GSH metabolism was observed in TK6 cells. NO. led to an increase in
GSSG levels similar to that observed in CHO-AA8 cells, however, a decrease in GSH levels,
no change in GSSR levels, and higher levels of toxicity were also found, suggesting that
NO-treated TK6 cells are not as competent in GSH homeostasis as CHO cells. We conclude
that GSH is involved in protecting cells from killing by NO. and that both de novo
synthesis of GSH and GSSG reduction are important in maintaining an adequate level of
protection for the cells.
- Language of Publication
- English
- Unique Identifier
- 97041531
- MeSH Heading (Major)
- Buthionine Sulfoximine|*PD; Carmustine|*PD; Glutathione|AA/*ME; Nitric Oxide|*TO;
Oxidative Stress|*
- MeSH Heading
- Animal; Cell Line; Cell Survival|DE; CHO Cells; Enzyme Inhibitors|PD; Glutamate-Cysteine
Ligase|AI; Glutathione Reductase|AI; Hamsters; Human; Reactive Oxygen Species; Support,
U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0891-5849
- Country of Publication
- UNITED STATES
Record 28 from database: MEDLINE
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- Title
- Comparison of sulfur amino acid utilization for GSH synthesis between HepG2 cells and
cultured rat hepatocytes.
- Author
- Lu SC; Huang HY
- Address
- Department of Medicine, University of Southern California School of Medicine, Los
Angeles 90033.
- Source
- Biochem Pharmacol, 1994 Mar, 47:5, 859-69
- Abstract
- HepG2 cells are widely used as a model of human hepatocytes for studies of drug
metabolism and toxicity. However, GSH metabolism in HepG2 cells is poorly characterized.
This report describes the utilization of sulfur amino acids for GSH synthesis in HepG2
cells. In contrast to primary cultures of rat hepatocytes, which rely mostly on methionine
for GSH synthesis, HepG2 cells use cystine. Their inability to utilize methionine for GSH
synthesis was not due to lack of methionine uptake or low cellular ATP levels, but rather
to the lack of S-adenosyl-methionine synthetase activity. When HepG2 cells were cultured
overnight in medium containing cystine as the only sulfur amino acid, addition of
glutamate or acivicin had minimal to no effect on cell GSH; however, addition of threonine
significantly depleted cell GSH. When cystine (0.18 mM) uptake was measured, glutamate
(2.5 mM), which inhibited cystine uptake in cultured rat hepatocytes, had a minimal effect
in HepG2 cells. Instead, threonine (20 mM) strongly inhibited the apparent uptake of
cystine by HepG2 cells. Strong inhibition by threonine of apparent cystine uptake was
actually due to inhibition of cysteine uptake, which resulted from
GSH-cystine mixed disulfide exchange. Radio-HPLC confirmed this. After incubating cells
with [35S]cystine (0.18 mM) for 10 min, the total counts inside the cell matched the
counts in the uptake medium in the form of GSH-cysteine mixed disulfide.
Finally, HepG2 cells took up cysteine by both Na(+)-dependent and
-independent mechanisms. The former exhibited high affinity and low capacity, whereas the
latter exhibited the opposite. At a physiologic concentration of cysteine
(10 microM), 68% of cysteine uptake occurred via the Na(+)-dependent
system and 32% via system L1.
- Language of Publication
- English
- Unique Identifier
- 94183303
- MeSH Heading (Major)
- Amino Acids, Sulfur|*ME; Glutathione|AN/*BI; Hepatoblastoma|*ME; Liver|CY/*ME; Liver
Neoplasms|*ME
- MeSH Heading
- Adenosine Triphosphate|AN; Animal; Cell Count; Comparative Study; Cysteine|ME;
Cystine|ME; Human; Male; Methionine|ME; Rats; Rats, Sprague-Dawley;
S-Adenosylmethionine|PH; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Tumor
Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-2952
- Country of Publication
- ENGLAND
Record 29 from database: MEDLINE
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- Title
- Cleavage of the human C5A receptor by proteinases derived from Porphyromonas gingivalis:
cleavage of leukocyte C5a receptor.
- Author
- Jagels MA; Ember JA; Travis J; Potempa J; Pike R; Hugli TE
- Address
- Department of Immunology, Scripps Research Institute, La Jolla, California 92037, USA.
- Source
- Adv Exp Med Biol, 1996, 389:, 155-64
- Abstract
- The anaerobic bacteria P. gingivalis has been implicated as a primary causative agent in
adult periodontitis. Several proteinases are produced by this bacteria and it is suggested
that they contribute to virulence and to local tissue injury resulting from infection by
P. gingivalis. Collagenases and cysteine proteinases (i.e., the
gingipains) have been characterized as the predominant vesicular enzymes produced by this
bacterium. It has been shown that an arginine-specific cysteine
proteinase from P. gingivalis, called gingipain-1 or Arg-gingipain, can selectively cleave
complement components C3 and C5. In the case of C5, cleavage by Arg-gingipain results in
the generation of C5a, a potent chemotactic factor for PMNs. Since these bacterial
proteinases are capable of generating pro-inflammatory factors at sites of infection, we
examined the possibility that gingipains or other proteinases from this bacterium might
attack or destroy cell surface proteins, such as receptor molecules. Using an
affinity-purified rabbit antibody raised against residues 9-29 of the C5a receptor (i.e.,
C5aR; CD88), the signal transmitting element for the pro-inflammatory mediator C5a, we
demonstrated that the mixture of proteinases in P. gingivalis vesicles cleaves the C5a
receptor on human neutrophils. This vesicular proteinase activity did not require cysteine
activation which indicates that proteinases other than the gingipains may be responsible
for cleavage of the C5aR molecule. in addition, the purified Lys-gingipain, but not
Arg-gingipain, also cleaved C5aR on the human neutrophils. The N-terminal region of CaR
(residues 9-29, PDYGHYDDKDTLDLNTPVDKT) was readily cleaved by chymotrypsin, but not by
trypsin, despite the presence of potential trypsin (i.e., lysyl-X) cleavage sites. The
specific sites of C5aR 9-29 peptide cleavage were determined by mass spectroscopy for both
chymotrypsin and Lys-gingipain. These studies suggest that the proteolytic activity in the
bacterial vesicles that is responsible for cleaving C5aR is primarily a non-tryptic
proteinase, distance from either Arg- or Lys-gingipain. Consequently, there appear to be
additional proteinase(s) in the vesicles that attacks the cell surface molecule C5aR which
are not the same (i.e., Arg- and Lys-gingipain) as were shown to generate pro-inflammatory
activity from complement components C3 and C5. Evidence that the proteinases which attack
the inflammatory precursor molecules (i.e., C3 and C5) exhibit different specificities
than those that attack receptors to these bioactive complement products makes a
particularly interesting story of how this bacteria avoids major host defense mechanisms.
It is well known that generation of pro-inflammatory factors such as C3a and C5a at
extra-vascular sites can promote edema, leukocyte recruitment and cellular activation
responses that could lead to the release of toxic oxygen products and to phagocytosis of
the bacteria. Destruction of receptors to these cellular activating factors generated by
bacterial proteinases may eliminate the ability of these (i.e., complement-derived) and
other mediators to carry out their anti-bacterial actions and thereby limit the host's
defense mechanisms in responses to the infecting bacteria. The concept of anti-bacterial
responses (i.e., oxygen radical generation and phagocytosis) being effectively eliminated
at the injury site, by bacterial proteinases acting at the cellular receptor level, has
not been studied in detail. In this case, the situation is particularly unusual because,
once the bacterial gingipains generate potent plasma-derived inflammatory factors that can
enhance edema and deliver essential nutrients to the bactgeria, other bacterial
proteinases may destsroy their cellular receptors. These receptors transmit the signal
activation mechanisms in the infiltrating cells that elicit bacterial killing.(ABSTRACT
TRUNCATED)
- Language of Publication
- English
- Unique Identifier
- 97014171
- MeSH Heading (Major)
- Antigens, CD|*BL; Complement 5a|*; Cysteine Proteinases|*BL/IP;
Hemagglutinins|*BL/IP; Leukocytes|*ME; Peptide Peptidohydrolases|*BL/IP; Porphyromonas
gingivalis|*EN; Receptors, Complement|*BL
- MeSH Heading
- Amino Acid Sequence; Human; Molecular Sequence Data; Signal Transduction|PH; Support,
Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0065-2598
- Country of Publication
- UNITED STATES
Record 30 from database: MEDLINE
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- Title
- Glutathione transferase activity and formation of macromolecular adducts in two cases of
acute methyl bromide poisoning.
- Author
- Garnier R; Rambourg Schepens MO; Müller A; Hallier E
- Address
- Centre Anti-poisons, Clinique, Interuniversitaire de MÆedicine du Travail, Paris,
France.
- Source
- Occup Environ Med, 1996 Mar, 53:3, 211-15
- Abstract
- OBJECTIVES: To determine the activity of glutathione transferase and to measure the
S-methylcysteine adducts in blood proteins, after acute inhalation exposure to methyl
bromide. To examine the influence of the polymorphism of glutathione-S-transferase theta
(GSTT1) on the neurotoxicity of methyl bromide. METHODS: Two workers acutely exposed to
methyl bromide with inadequate respiratory protective devices were poisoned. Seven weeks
after the accident, blood samples were drawn from both patients, for measurement of
glutathione transferase activity in erythrocytes (conjugator status--that is, GSTT1
phenotype) and measurement of binding products of methyl bromide with blood proteins.
Conjugator status was determined by a standard procedure. The binding product of methyl
bromide, S-methylcysteine, was measured in globin and albumin. RESULTS: Duration and
intensity of exposure were identical for both patients as they worked together with the
same protective devices and with similar physical effort. However, one patient had very
severe poisoning, whereas the other only developed mild neurotoxic symptoms. The first
patient was a "conjugator" with normal glutathone transferase activity, whereas
this activity was undetectable in the erythrocytes of the second patient, who consequently
had higher concentrations of S-methylcysteine adduct in albumin (149 v 91 nmol/g protein)
and in globin (77 v 30 nmol/g protein). CONCLUSIONS: Methyl bromide is genotoxic and
neurotoxic. Its genotoxicity seems to be the consequence of the alkylating activity of the
parent compound, and conjugation to glutathione has a protective effect. The data
presented here suggest a different mechanism for methyl bromide neurotoxicity which could
be related to the transformation of methylglutathione into toxic metabolites such as
methanethiol and formaldehyde. If such metabolites are the ultimate toxic species,
N-acetylcysteine treatment could have a toxifying rather than a detoxifying effect.
- Language of Publication
- English
- Unique Identifier
- 96247008
- MeSH Heading (Major)
- Cysteine|*AA/BL; Glutathione Transferase|*BL; Hydrocarbons,
Brominated|*BL/*PO; Occupational Exposure|*AE
- MeSH Heading
- Acute Disease; Adult; Case Report; Fumigation|AE; Human; Male; Nervous System
Diseases|CI; Phenotype
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 1351-0711
- Country of Publication
- ENGLAND
Record 31 from database: MEDLINE
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- Title
- Elevation of homocysteine and excitatory amino acid neurotransmitters in the CSF of
children who receive methotrexate for the treatment of cancer.
- Author
- Quinn CT; Griener JC; Bottiglieri T; Hyland K; Farrow A; Kamen BA
- Address
- Department of Pediatrics, The University of Texas Southwestern Medical Center, Dallas
75235-9063, USA.
- Source
- J Clin Oncol, 1997 Aug, 15:8, 2800-6
- Abstract
- PURPOSE: Folate deficiency, either by diet or drug, increases plasma homocysteine (Hcy).
Hcy damages cerebrovascular endothelium, and hyperhomocysteinemia is a risk factor for
stroke. Hcy is metabolized to excitatory amino acid (EAA) neurotransmitters, such as
homocysteic acid (HCA) and cysteine sulfinic acid (CSA), which may cause
seizures and excitotoxic neuronal death. We postulated that excess Hcy and EAA
neurotransmitters may partly mediate methotrexate (MTX)-associated neurotoxicity. PATIENTS
AND METHODS: In this retrospective analysis, we used high-performance liquid
chromatography (HPLC) to measure Hcy, HCA, and CSA in CSF from two groups of children: (1)
a control group of patients with no MTX exposure, and (2) a treatment group of patients
who had received MTX no more than 7 days before a scheduled lumbar puncture. RESULTS: The
treatment group had a significantly (P = .0255) greater concentration of Hcy in CSF (0.814
micromol/L +/- 0.215 [mean +/- SEM], n = 23) than the control group (0.210 micromol/L +/-
0.028, n = 34). HCA and CSA were not detected in CSF from control patients (n = 29);
however, MTX caused marked accumulation of CSF HCA (119.1 micromol/L +/- 32.0, n = 16) and
CSA (28.4 micromol/L +/- 7.7, n = 16) in the treatment group. Patients with neurologic
toxicity at the time of lumbar puncture had many of the highest concentrations of Hcy,
HCA, and CSA. CONCLUSION: These data support our hypothesis that MTX-associated
neurotoxicity may be mediated by Hcy and excitotoxic neurotransmitters.
- Language of Publication
- English
- Unique Identifier
- 97398197
- MeSH Heading (Major)
- Antimetabolites, Antineoplastic|AE/*TU; Excitatory Amino Acids|*CF; Homocysteine|AA/*CF;
Methotrexate|AE/*TU; Neoplasms|*CF/DT
- MeSH Heading
- Central Nervous System|DE; Child; Chromatography, High Pressure Liquid; Cysteine|AA/CF;
Human; Retrospective Studies; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0732-183X
- Country of Publication
- UNITED STATES
Record 32 from database: MEDLINE
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- Title
- Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity.
- Author
- Lauterburg BH; Velez ME
- Address
- Department of Clinical Pharmacology, University of Berne, Switzerland.
- Source
- Gut, 1988 Sep, 29:9, 1153-7
- Abstract
- Patients chronically abusing ethanol are more susceptible to the hepatotoxic effects of
paracetamol. This could be due to an increased activation of the drug to a toxic
metabolite or to a decreased capacity to detoxify the toxic metabolite by conjugation with
glutathione (GSH). To test these hypotheses paracetamol 2 g was administered to five
chronic alcoholics without clinical evidence of alcoholic liver disease and five control
subjects. The urinary excretion of cysteine- plus
N-acetyl-cysteine-paracetamol, the two major products of detoxification of the reactive
metabolite of paracetamol, was not significantly higher in chronic alcoholics arguing
against a substantially increased metabolic activation of paracetamol. Chronic alcoholics
had significantly lower plasma concentrations of GSH than healthy volunteers, however
(4.35 (1.89) microM v 8.48 (2.68) microM, p less than 0.05) before the administration of
paracetamol, and plasma GSH reached lower concentrations in the alcoholics after
paracetamol (2.40 (1.36) v 6.26 (2.96) microM). In a group of patients with alcoholic
hepatitis intrahepatic GSH was significantly lower than in patients with chronic
persistent hepatitis and patients with non-alcoholic cirrhosis, suggesting that low plasma
GSH in alcoholics reflects low hepatic concentrations of GSH. The data indicate that low
GSH may be a risk factor for paracetamol hepatotoxicity in alcoholics because a lower dose
of paracetamol will be necessary to deplete GSH below the critical threshold concentration
where hepatocellular necrosis starts to occur.
- Language of Publication
- English
- Unique Identifier
- 89065417
- MeSH Heading (Major)
- Acetaminophen|*AE/ME; Alcoholism|*CO/ME; Glutathione|BL/*DF/ME; Hepatitis, Toxic|*ET/ME
- MeSH Heading
- Cysteine|UR; Human; Liver|ME; Male; Risk Factors; Support, Non-U.S.
Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0017-5749
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 103-90-2 (Acetaminophen); 4371-52-2 (Cysteine); 70-18-8 (Glutathione)
Record 33 from database: MEDLINE
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- Title
- Oxidative stress and thiol depletion in plasma and peripheral blood lymphocytes from
HIV-infected patients: toxicological and pathological implications.
- Author
- Walmsley SL; Winn LM; Harrison ML; Uetrecht JP; Wells PG
- Address
- Department of Medicine, University of Toronto, Ontario, Canada.
- Source
- AIDS, 1997 Nov, 11:14, 1689-97
- Abstract
- OBJECTIVES: To determine, first, whether the plasma and lymphocytes of HIV-positive
individuals and AIDS patients have alterations in the major thiols glutathione and cysteine,
and/or their oxidative disulphide and mixed disulphide products; and, secondly, whether
thiol/disulphide status differs in patients with sulphonamide drug hypersensitivity
reactions. DESIGN: Thiols provide critical cellular defence against toxic drug reactive
intermediates and endogenous oxidative stress, and may modulate HIV replication.
Glutathione is reported to be low in HIV-positive individuals and AIDS patients, but this
is controversial and the mechanism responsible is unknown. Also unknown is whether altered
thiol/disulphide status determines the predisposition of HIV-positive and AIDS patients to
drug reactions. METHODS: Thiols and disulphides were measured by high-performance liquid
chromatography. RESULTS: Both plasma thiols were decreased by approximately 58% in
HIV-positive individuals and AIDS patients compared with uninfected controls (P <
0.05), with increases of up to threefold in oxidized products (P < 0.05). Similarly, in
lymphocytes, thiols were decreased by 30-35% (P < 0.05), with apparent increases in
oxidized products. For both glutathione and cysteine, the
thiol/disulphide ratios also were decreased (P < 0.05). The plasma and lymphocyte
glutathione thiol/disulphide ratios were highly correlated (r = 0.7661; P = 0.0001) among
all subjects. No parameters differed in patients with drug reactions, or with
antiretroviral therapy. CONCLUSIONS: The enhanced thiol oxidation in HIV-positive
individuals and AIDS patients indicates oxidative stress, which also contributes to thiol
depletion, and may enhance damage to macromolecular targets. These mechanisms may
contribute to enhanced viral replication and other pathological outcomes. HIV-positive
individuals' and AIDS patients' predisposition to drug hypersensitivity reactions appears
to be unrelated to thiol/disulphide status.
- Language of Publication
- English
- Unique Identifier
- 98048034
- MeSH Heading (Major)
- Cysteine|AA/*BL; Disulfides|*BL; Glutathione|AA/*BL; HIV
Infections|*BL; Oxidative Stress|*
- MeSH Heading
- Analysis of Variance; Drug Hypersensitivity; Glutathione Disulfide|BL; Human;
Leukocytes, Mononuclear|CY/ME; Sulfonamides|AE; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0269-9370
- Country of Publication
- UNITED STATES
Record 34 from database: MEDLINE
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- Title
- Differential activity of bcl-2 and ICE enzyme family protease inhibitors on Fas and
puromycin-induced apoptosis of glioma cells.
- Author
- Schlapbach R; Fontana A
- Address
- University Hospital Zurich, Section of Clinical Immunology, Switzerland.
- Source
- Biochim Biophys Acta, 1997 Nov, 1359:2, 174-80
- Abstract
- Fas ligand is a potent inducer of apoptosis in human glioma cells by the Fas/Fas ligand
pathway. With comparable efficiency, metalloprotease inhibitors including puromycin and
bestatin induce apoptosis in glioma cells. To evaluate the involvement of potential
components involved in Fas ligand- and metalloprotease inhibitor-induced apoptosis, we
investigated the effect of anti human Fas antibody, soluble Fas ligand and puromycin on
cultures of human malignant glioma cell lines (LN-18, LN-229, T98G). Stimulation with Fas
ligand lead to apoptotic cell death within 16 h. Costimulation with the translational
inhibitor cycloheximide and the transcription blocker actinomycin D did not reduce Fas
ligand toxicity. In contrast, apoptosis induced by puromycin was blocked by cycloheximide
and decreased by subtoxic doses of actinomycin D in all three gliomas. Whereas inhibition
of caspase activity with the general inhibitor zVAD-fmk resulted in a complete block of
Fas ligand-induced cell death, puromycin-mediated apoptosis was found to be unaffected by
zVAD-fmk as well as by more specific inhibitors for caspase-1 (Interleukin-1 beta
converting enzyme) and caspase-3 (CPP32/Yama). Other prominent components involved in many
apoptotic pathways as bcl-2 and reactive oxygen intermediates were also examined. Bcl-2
which protects glioma cells from Fas ligand-induced cell death, was shown to have only a
small protective effect on puromycin-induced apoptosis. The tested radical scavengers did
not reduce Fas- or puromycin-mediated killing of human glioma cells.
- Language of Publication
- English
- Unique Identifier
- 98072472
- MeSH Heading (Major)
- Apoptosis|*DE; Cysteine Proteinase Inhibitors|*PD; Cysteine
Proteinases|*ME; Glioma|ME/*PA; Proto-Oncogene Proteins c-bcl-2|GE/*ME
- MeSH Heading
- Amino Acid Chloromethyl Ketones|PD; Antibodies, Monoclonal|IM; Antigens, CD95|IM/ME;
Cell Survival|DE; Cycloheximide|PD; Dactinomycin|PD; Free Radical Scavengers|PD; Human;
Leucine|AA/PD; Membrane Glycoproteins|ME; Oligopeptides|PD; Puromycin|PD; Support,
Non-U.S. Gov't; Transfection|GE; Tumor Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-3002
- Country of Publication
- NETHERLANDS
Record 35 from database: MEDLINE
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- Title
- N-acetylcysteine treatment and the risk of toxic reactions to
trimethoprim-sulphamethoxazole in primary Pneumocystis carinii prophylaxis in HIV-infected
patients.
- Author
- Akerlund B; Tynell E; Bratt G; Bielenstein M; Lidman C
- Address
- Department of Infectious Diseases, Karolinska Institute, Huddinge University Hospital,
Sweden.
- Source
- J Infect, 1997 Sep, 35:2, 143-7
- Abstract
- In a randomized double blind placebo controlled trial, HIV sero-positive patients with
CD4+ cell count less than 200 x 10(6)/l or an AIDS diagnosis were evaluated for drug
reactions to trimethoprim-sulphamethoxazole (TMP-SMX) during treatment, including
pretreatment, with N-acetylcysteine (NAC) 800 mg daily or placebo. TMP-SMX (one
double-strength tablet containing 160 mg of trimethoprim and 800 mg of sulphamethoxazole)
was given three times weekly as primary Pneumocystis carinii (PCP) prophylaxis. Thirty
percent (n = 15) of the patients experienced adverse reactions 8-20 (mean 12.7) days after
starting with TMP-SMX. At entry, low cysteine and glutathione levels in
plasma were found in the HIV-positive patients. Age, sex, CD4+ count, plasma cysteine
and glutathione levels were not risk factors for adverse reactions to TMP-SMX. However,
concomitant therapy with nucleoside analogues was associated with increased risk for
TMP-SMX reactions. Oral NAC 800 mg daily was well tolerated, but replenished neither cysteine
nor glutathione levels in plasma. NAC 800 mg/day did not significantly decrease the risk
of adverse reactions to TMP-SMX in this study, and could thus not be recommended for this
purpose. A prolonged pretreatment period and/or higher dose of NAC may be necessary for
clinical effect.
- Language of Publication
- English
- Unique Identifier
- 98014439
- MeSH Heading (Major)
- Acetylcysteine|*TU; Anti-Infective Agents|*AE; AIDS-Related Opportunistic
Infections|*PC; Pneumocystis carinii|*; Pneumonia, Pneumocystis carinii|*PC;
Trimethoprim-Sulfamethoxazole Combination|*AE
- MeSH Heading
- Adult; Comparative Study; Cysteine|DF; Exanthema|CI/PC; Female;
Fever|CI/PC; Glutathione|BL; Human; Male; Support, Non-U.S. Gov't
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
- ISSN
- 0163-4453
- Country of Publication
- ENGLAND
Record 36 from database: MEDLINE
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- Title
- Activity and distribution of the cysteine prodrug activating enzyme,
5-oxo-L-prolinase, in human normal and tumor tissues.
- Author
- Srivenugopal KS; Ali Osman F
- Address
- Department of Experimental Pediatrics, University of Texas, M.D. Anderson Cancer Center,
Houston 77030, USA.
- Source
- Cancer Lett, 1997 Jul, 117:1, 105-11
- Abstract
- 5-Oxo-L-prolinase (OPase), a key enzyme of the gamma-glutamyl cycle, has the ability to
metabolize L-2-oxothiazolidine-4-carboxylic acid (OTC) to cysteine, and
thereby increase intracellular glutathione (GSH) levels. This strategy of GSH elevation
can be potentially exploited to reduce normal tissue toxicity of anticancer agents,
provided that sufficient differences exist in OPase levels between normal and malignant
tissues. In this study, therefore, we quantitated OPase activity in primary specimens of
matched and unmatched human normal and tumor (lung, breast, kidney, colon and ovary)
tissues using a newly developed non-radioactive OPase assay, based on the production of cysteine
from OTC. The rank order of OPase activity in extracts of 24 normal tissues examined was
kidney > lung, breast and colon > ovary. OPase activity was present in all 37 tumor
samples, but at variable levels. Tumor OPase levels were generally equivalent to those in
their normal tissue counterparts, with the notable exception of Wilms' tumors, which had
markedly lower levels than normal kidney (P < 0.02). However, when 14 matched tumor and
adjacent normal tissues were compared, OPase levels were significantly higher in normal
specimens than tumors for individual patients (P < 0.005). These higher normal
tissue/tumor OPase ratios suggest that OTC may be useful in decreasing normal tissue
toxicity, at least, for some tissues during cancer therapy.
- Language of Publication
- English
- Unique Identifier
- 97377068
- MeSH Heading (Major)
- Cysteine|*ME; Neoplasms|*EN; Pyroglutamate Hydrolase|*ME
- MeSH Heading
- Human; Prodrugs|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Thiazoles|ME
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0304-3835
- Country of Publication
- IRELAND
Record 37 from database: MEDLINE
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- Title
- Glutathione in human melanoma cells. Effects of cysteine, cysteine
esters and glutathione isopropyl ester.
- Author
- Karg E; Tunek A; Brötell H; Hallberg A; Rosengren E; Rorsman H
- Address
- Department of Dermatology, University of Lund, Sweden.
- Source
- J Dermatol Sci, 1990 Jan, 1:1, 39-45
- Abstract
- Thiols are of great importance for the regulation of many cellular functions including
metabolism, transport and cell protection. In this study the usefulness of L-cysteine
methyl and octyl esters, of N,S-diacetyl-L-cysteine methyl ester and
glutathione isopropyl ester as cellular cysteine and GSH delivery systems
was investigated in the human IGR 1 melanoma cell line. The L-cysteine
methyl and octyl esters proved to be highly toxic to the cells. Treatment of the cultures
with 1 mM N,S-diacetyl-L-cysteine methyl ester or 3 mM glutathione
isopropyl ester for 24 h resulted in marked elevation of the cellular glutathione level
without apparent or with slight cell loss, respectively. Thus the administration of the
latter two compounds seems to be suitable for inducing GSH elevation in the cultured
melanoma cells.
- Language of Publication
- English
- Unique Identifier
- 91175649
- MeSH Heading (Major)
- Glutathione|AA/*ME/PD; Melanoma|ME/*PA; Skin Neoplasms|ME/*PA
- MeSH Heading
- Acetylcysteine|AA/PD; Cysteine|AA/ME/PD; Expectorants|PD; Human;
Support, Non-U.S. Gov't; Tumor Cells, Cultured|DE/ME/PA
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0923-1811
- Country of Publication
- NETHERLANDS
- CAS Registry/EC Number
- 0 (Expectorants); 19547-88-7 (N,S-diacetylcysteine methyl ester); 2485-62-3
(mecysteine); 4371-52-2 (Cysteine); 616-91-1 (Acetylcysteine); 70-18-8
(Glutathione); 94333-34-3 (cysteine octyl ester); 97451-46-2 (glutathione
monoisopropyl ester)
Record 38 from database: MEDLINE
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- Title
- Looking beneath the surface: the cell death pathway of Fas/APO-1 (CD95).
- Author
- Stanger BZ
- Address
- Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute,
Boston, Massachusetts 02115, USA.
- Source
- Mol Med, 1996 Jan, 2:1, 7-20
- Abstract
- SUMMARY: The biochemical basis of programmed cell death is poorly understood in mammals.
The cell surface receptor Fas/APO-1 (CD95) is one molecule known to be central to a number
of mammalian cell death processes. Several studies in the past year have led to insights
about the role of Fas/APO-1 in vivo and have also given some clues about the biochemical
components of the Fas/APO-1 death pathway. This article reviews those studies and discuss
models of Fas/APO-1 signaling and function. BACKGROUND: Cell death occurs as a normal
process in a wide variety of developmental and homeostatic contexts in metazoan organisms
(1); it represents the timely and appropriate fate for many or even the majority of cells
born in certain organ systems. Despite the importance and ubiquitous nature of such
physiologic, or "programmed", cell death, little is known about the molecular
events that mediate this process. That a conserved biochemical pathway exists is suggested
by the observation that programmed cell death is almost always accompanied by a consistent
set of morphologic changes, an appearance known as apoptosis (2). The identification of
the genes that control programmed cell death in higher eukaryotes has been hampered by
several inherent difficulties. First, the genetic tools so useful in dissecting cell death
pathways in Caenorhabditis elegans (3) and Drosophila (4) have not been available in
higher eukaryotes. Second, the death-inducing properties of such genes makes genetic
selection an impractical means of identification. Third, it appears that many cell death
genes are constitutively expressed and present in an inactive form (5), making it unlikely
that they could be discovered by techniques relying upon differential gene expression.
Finally, genes identified by virtue of an ability to induce death when overexpressed must
be subjected to rigorous criteria to determine whether the cell death is of physiologic
importance, since it is likely that overexpression of certain proteins may lead to toxic
effects that are distinct from the in vivo roles of those proteins. Two approaches to date
have yielded the most information about cell death processes: (i) identification of cell
death genes by classical genetic means coupled with characterization of their mammalian
homologs and (ii) screening for proteins capable of inducing cell death directly in
mammalian cells. The Fas antigen/APO-1 is an example of a protein discovered using the
latter approach, as it was first discovered as an inducer of cell death and later shown to
be necessary and sufficient for certain programmed deaths in vivo. More recent studies
have connected Fas to elements of cell death pathways in other species. It has been
proposed that Fas is related to the Drosophila cell death protein Reaper, and that in
signaling cell death Fas relies upon a relative of the C. elegans cell death protein
CED-3. Fas may therefore represent an evolutionarily conserved component of a universal
cell death pathway.
- Language of Publication
- English
- Unique Identifier
- 97056190
- MeSH Heading (Major)
- Antigens, CD95|*ME; Apoptosis|DE/*GE
- MeSH Heading
- Animal; Conserved Sequence|GE; Cysteine Proteinases|GE/ME; Evolution,
Molecular; Human; Mammals|ME/PH; Models, Genetic; Models, Molecular; Phosphoric Monoester
Hydrolases; Phosphotransferases; Sequence Homology; Signal Transduction
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1076-1551
- Country of Publication
- UNITED STATES
Record 39 from database: MEDLINE
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- Title
- Human rhinovirus 2A proteinase mutant and its second-site revertants.
- Author
- Luderer Gmach M; Liebig HD; Sommergruber W; Voss T; Fessl F; Skern T; Kuechler E
- Address
- Institut fÂur Biochemie der Universitaet Wien, Vienna, Austria.
- Source
- Biochem J, 1996 Aug, 318 ( Pt 1):, 213-8
- Abstract
- The 2A proteinases of human rhinoviruses are cysteine proteinases with
marked similarities to serine proteinases. In the absence of a three-dimensional
structure, we developed a genetical screening system for proteolytic activity and
identified Phe-130 as a key residue. The mutation Phe-130-->Tyr almost completely
inhibited enzyme activity at 37 degrees C; activity was, however, partially restored by
the following exchanges: Ser-27-->Pro, His-135-->Arg or His-137-->Arg. To
investigate this phenotypic reversion, 2A proteinases with the mutations Phe-130-->Tyr,
Phe-130-->Tyr/His-135-->Arg, Phe-130-->Tyr/His-137-->Arg, His-135-->Arg or
His-137-->Arg were expressed in Escherichia coli and purified. None of these mutations
affected the affinity of the enzyme for a peptide substrate. However, the
temperature-dependence of enzyme activity, as assayed by cleavage of a peptide substrate
and by monitoring the toxicity of the proteinases towards the E. coli strain BL21(DE3),
and the structural stability, as monitored by 8-anilino-I-naphthalenesulphonic acid
fluorescence and CD spectrometry, were affected. The thermal transition temperatures for
both the activity and the stability of the Phe-130-->Tyr 2A proteinase were reduced by
about 17 degrees C compared with the wild-type enzyme. The presence of the additional
mutations His-135-->Arg or His-137-->Arg in the Phe-130-->Tyr mutant increased
temperature stability by 3 degrees C and 6 degrees C respectively. Thus essential
interactions exist within the C-terminal domain of human rhinoviral 2A proteinases which
contribute to the overall stability and integrity of the enzyme.
- Language of Publication
- English
- Unique Identifier
- 96358508
- MeSH Heading (Major)
- Cysteine Proteinases|CH/*GE/*ME; Rhinovirus|*EN
- MeSH Heading
- Binding Sites; Circular Dichroism; Enzyme Stability; Escherichia coli|GE; Genes, Viral;
Genetic Screening; Human; Kinetics; Lac Operon; Mutagenesis, Site-Directed; Point
Mutation; Protein Denaturation; Recombinant Proteins|GE/ME; Support, Non-U.S. Gov't;
Temperature; Transformation, Genetic
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0264-6021
- Country of Publication
- ENGLAND
Record 40 from database: MEDLINE
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- Title
- Effect of selenium compounds and thiols on human mammary tumor cells.
- Author
- Yan L; Yee JA; Boylan LM; Spallholz JE
- Address
- Center for Food and Nutrition, Texas Tech University, Lubbock 79409.
- Source
- Biol Trace Elem Res, 1991 Aug, 30:2, 145-62
- Abstract
- The effect on cell viability and growth rate of sodium selenite, selenocystine, sodium
selenate, and selenomethionine at selenium concentrations of 6.25 and 12.5 uM was studied
in vitro on cells of the human mammary tumor cell line HTB123/DU4475. Selenite and
selenocystine affected both cell viability and growth rate of the tumor cells at these
selenium concentrations. Selenite and selenocystine decreased intracellular glutathione
concentrations, but did not affect tumor cell glutathione peroxidase activity. After six
days of exposure to either selenate or selenomethionine, the viability of tumor cells
remained stable, but cell growth, as measured by numbers of cells, was retarded. Neither
selenate nor selenomethionine produced changes in concentrations of intracellular
glutathione. The toxic effect of selenite on tumor cells was enhanced by addition of 0.25
mM glutathione to the growth medium. Preincubation of the tumor cells with 62.5 uM
buthionine sulfoximine decreased cellular glutathione to 15% of controls at 24 h and
enhanced the toxicity of selenite toward the tumor cells. Glutathione, 2-mercaptoethanol,
and L-cysteine were all toxic to the tumor cells in a dose-dependent
manner.
- Language of Publication
- English
- Unique Identifier
- 92153614
- MeSH Heading (Major)
- Breast Neoplasms|EN/*PA; Organoselenium Compounds|*PD; Selenium|*PD; Sulfhydryl
Compounds|*PD
- MeSH Heading
- Aged; Antimetabolites|PD; Cell Survival|DE; Cysteine|AA/PD; Female;
Glutathione|ME/PD; Glutathione Peroxidase|AI/ME; Human; Mercaptoethanol|PD; Methionine
Sulfoximine|AA/PD; Selenomethionine|PD; Support, Non-U.S. Gov't; Trypan Blue; Tumor Cells,
Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0163-4984
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 1.11.1.9 (Glutathione Peroxidase); 0 (Antimetabolites); 0 (Organoselenium Compounds);
0 (Sulfhydryl Compounds); 10102-18-8 (Sodium Selenite); 10236-58-5 (Selenocysteine);
13410-01-0 (sodium selenate); 1464-42-2 (Selenomethionine); 1982-67-8 (Methionine
Sulfoximine); 4371-52-2 (Cysteine); 5072-26-4 (Buthionine Sulfoximine);
60-24-2 (Mercaptoethanol); 70-18-8 (Glutathione); 72-57-1 (Trypan Blue); 7782-49-2
(Selenium); 7783-00-8 (selenious acid)
Record 41 from database: MEDLINE
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- Title
- D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation
status and HLA-DR3.
- Author
- Emery P; Panayi GS; Huston G; Welsh KI; Mitchell SC; Shah RR; Idle JR; Smith RL; Waring
RH
- Address
-
- Source
- J Rheumatol, 1984 Oct, 11:5, 626-32
- Abstract
- Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine,
displays a skewed distribution within a population. In 66 patients with rheumatoid
arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p
less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05),
appeared to be an independent risk factor of most importance in the group with extensive
sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or
impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of
RA patients was increased compared to that in a previous population study and requires
further investigation. Our findings explain a number of the toxic phenomena associated
with D-penicillamine administration in RA.
- Language of Publication
- English
- Unique Identifier
- 85082881
- MeSH Heading (Major)
- Arthritis, Rheumatoid|*DT/GE/ME; Carbocysteine|*ME; Cysteine|*AA;
Histocompatibility Antigens Class II|*GE; Penicillamine|*AE/ME/TU
- MeSH Heading
- Adult; Aged; Biotransformation; Female; Human; Male; Middle Age; Risk
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0315-162X
- Country of Publication
- CANADA
- CAS Registry/EC Number
- 0 (Histocompatibility Antigens Class II); 0 (HLA-DR3 Antigen); 0 (HLA-DR4 Antigen);
2387-59-9 (Carbocysteine); 4371-52-2 (Cysteine); 52-67-5 (Penicillamine)
Record 42 from database: MEDLINE
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- Title
- The influence of the protector thiol L-cystein on the toxic and therapeutic responses of
stabilized "activated" cyclophosphamide
(4-(S-ethanol)-sulfido-cyclophosphamide).
- Author
- Voelcker G; Laber P; Rockinger H; Wientzek C; Hohorst HJ
- Address
-
- Source
- Invest New Drugs, 1984, 2:2, 253-9
- Abstract
- The influence of L-cystein on the toxic and therapeutic responses of
4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated"
cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides
hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The
antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in
nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in
rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is
decreased by the protector thiol L-cystein. Simultaneous application of double molar
amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic
activity is not affected by this ratio of L-cystein so that the protector thiol increases
the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity
in nude mice and the therapeutic efficacy against the human xenograft. The perfusion
experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing
limb is only tolerated in combination with L-cystein.
- Language of Publication
- English
- Unique Identifier
- 84288388
- MeSH Heading (Major)
- Bladder Neoplasms|*DT; Cyclophosphamide|*AA/AD/TO/TU; Sarcoma, Yoshida|*DT
- MeSH Heading
- Animal; Cysteine; Female; Human; Lethal Dose 50; Male; Mice; Mice,
Nude; Neoplasm Transplantation; Perfusion, Regional; Rats; Rats, Inbred Strains;
Structure-Activity Relationship; Support, Non-U.S. Gov't; Transplantation, Heterologous
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0167-6997
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 4371-52-2 (Cysteine); 50-18-0 (Cyclophosphamide); 88746-71-8 (Asta Z
7557)
Record 43 from database: MEDLINE
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- Title
- Neuronal nitric oxide synthase, a modular enzyme formed by convergent evolution:
structure studies of a cysteine thiolate-liganded heme protein that
hydroxylates L-arginine to produce NO. as a cellular signal [published erratum appears in
FASEB J 1996 Jul;10(9):1107]
- Author
- Masters BS; McMillan K; Sheta EA; Nishimura JS; Roman LJ; Martasek P
- Address
- Department of Biochemistry, University of Texas Health Science Center at San Antonio
78284-7760, USA.
- Source
- FASEB J, 1996 Apr, 10:5, 552-8
- Abstract
- The nitric oxide synthases (NOS-I, neuronal, NOS-II, inducible, and NOS-III,
endothelial) are the most recent additions to the large number of heme proteins that
contain cysteine thiolate-liganded protoporphyrin IX heme prosthetic
groups. This group of oxygenating enzymes also includes one of the largest gene families,
that of the cytochromes P450, which have been demonstrated to be involved in the
hydroxylation of a variety of substrates, including endogenous compounds (steroids, fatty
acids, and prostaglandins) and exogenous compounds (therapeutic drugs, environmental
toxicants, and carcinogens). The substrates for cytochromes P450 are universally
hydrophobic while the physiological substrate for the nitric oxide synthases is the amino
acid L-arginine, a hydrophilic compound. This review will discuss the approaches being
used to study the structure and mechanism of neuronal nitric oxide synthase in the context
of its known prosthetic groups and regulation by Ca(2+)-calmodulin and/or
tetrahydrobiopterin (BH4).
- Language of Publication
- English
- Unique Identifier
- 96210310
- MeSH Heading (Major)
- Arginine|*ME; Isoenzymes|*CH/ME; Neurons|*EN; Nitric Oxide|*ME; Nitric-Oxide
Synthase|*CH/ME
- MeSH Heading
- Animal; Cysteine|CH; Free Radicals; Hemeproteins|CH; Human;
Hydroxylation
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0892-6638
- Country of Publication
- UNITED STATES
Record 44 from database: MEDLINE
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- Title
- Interleukin-1beta secretion is impaired by inhibitors of the Atp binding cassette
transporter, ABC1.
- Author
- Hamon Y; Luciani MF; Becq F; Verrier B; Rubartelli A; Chimini G
- Address
- Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, France.
- Source
- Blood, 1997 Oct, 90:8, 2911-5
- Abstract
- The production of interleukin-1beta (IL-1beta), a powerful mediator of inflammation, is
tightly regulated at several levels. However, in some pathologic conditions, a
pharmacologic treatment is required to control the toxicity of excessive extracellular
IL-1beta. Because of the heavy side effects of most therapies used in IL-1beta-mediated
pathologies, a goal of pharmacologic research is the development of selective
anti-IL-1beta drugs. We show here that the sulfonylurea glyburide, currently used in the
oral therapy of noninsulin dependent diabetes, is an inhibitor of IL-1beta secretion from
human monocytes and mouse macrophages. Glyburide reduces dramatically the recovery of
extracellular 17-kD IL-1beta in the absence of toxic effects on the cells and without
affecting the synthesis or processing of the IL-1beta precursor. IL-1beta belongs to the
family of leaderless secretory proteins released from the cell by a nonclassical secretory
route. In bacteria and yeast Atp binding cassette (ABC) transporters are involved in the
secretion of leaderless secretory proteins. Interestingly, glyburide blocks the anion
exchanger function of ABC1, a mammalian member of the family of ABC transporters. We thus
investigated the involvement of ABC1 in IL-1beta secretion, through the analysis of the
effects of drugs known to inhibit IL-1beta secretion, on the activity of ABC1 and in turn
the ability of known inhibitors of ABC1 of blocking IL-1beta secretion. Our data show that
IL-1beta secretion and the function of ABC1 as an anion exchanger are sensitive to the
same drugs, therefore suggesting an involvement of the ABC1 transporter in the secretion
of leaderless proteins in mammals.
- Language of Publication
- English
- Unique Identifier
- 98025873
- MeSH Heading (Major)
- Apoptosis|*; ABC Transporters|*AI; Glyburide|*PD; Glycoproteins|*AI; Interleukin-1|*SE
- MeSH Heading
- Acrylates|PD; Adenosine Triphosphate|PD; Animal; Anti-Inflammatory Agents,
Non-Steroidal|PD; Calcium Channel Blockers|PD; Cells, Cultured; Cysteine
Proteinases|ME; DIDS|PD; Human; Hypoglycemic Agents|PD; Indoles|PD;
Lipopolysaccharides|PD; Macrophages|DE/SE; Mice; Mice, Inbred CBA; Monocytes|DE/SE;
Recombinant Proteins|ME; Support, Non-U.S. Gov't; Verapamil|PD; Xenopus laevis
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-4971
- Country of Publication
- UNITED STATES
Record 45 from database: MEDLINE
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- Title
- Modulation of gene expression in subjects at risk for colorectal cancer by the
chemopreventive dithiolethione oltipraz.
- Author
- ODwyer PJ; Szarka CE; Yao KS; Halbherr TC; Pfeiffer GR; Green F; Gallo JM; Brennan J;
Frucht H; Goosenberg EB; Hamilton TC; Litwin S; Balshem AM; Engstrom PF; Clapper ML
- Address
- Fox Chase Cancer Center, Philadelpia, Pennsylvania 19111, USA.
- Source
- J Clin Invest, 1996 Sep, 98:5, 1210-7
- Abstract
- Prolonged exposure to mutagenic substances is strongly associated with an individual's
risk of developing colorectal cancer. Clinical investigation of oltipraz as a
chemopreventive agent is supported by its induction of the expression of detoxication
enzymes in various tissues, and its protective activity against the formation of
chemically induced colorectal tumors in animals. The goals of the present study were: to
determine if oltipraz could induce detoxicating gene expression in human tissues; to
identify effective non-toxic doses for more extensive clinical testing; and to establish a
relationship between effects in the colon mucosa and those in a more readily available
tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal
cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as
a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal
biopsies revealed increases in glutathione transferase activity at the lower dose levels.
These effects were not observed at the higher doses. More pronounced changes were observed
in detoxicating enzyme gene expression in both tissues at all doses. Peripheral
mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS)
and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and
declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression
in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for
DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and
DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells
and colon mucosa both at baseline and at peak. These findings demonstrate that the
administration of minimally toxic agents at low doses may modulate the expression of
detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore,
peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for
the transcriptional response of normal colon mucosa to drug administration.
- Language of Publication
- English
- Unique Identifier
- 96379671
- MeSH Heading (Major)
- Anticarcinogenic Agents|*TU; Colorectal Neoplasms|*GE/*PC; Gene Expression Regulation,
Neoplastic|*; Pyrazines|*TU
- MeSH Heading
- Adult; Aged; Aged, 80 and over; Chemoprevention; Colon|DE/EN; Comparative Study; Female;
Glutamate-Cysteine Ligase|AN; Human; Intestinal Mucosa|DE/EN; Leukocytes,
Mononuclear|DE/EN; Male; Metabolic Detoxication, Drug; Middle Age; Mutagenesis|DE; NAD(P)H
Dehydrogenase (Quinone)|AN; Risk; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 0021-9738
- Country of Publication
- UNITED STATES
Record 46 from database: MEDLINE
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- Title
- High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in
plasma and urine.
- Author
- Aebi S; Assereto R; Lauterburg BH
- Address
- Department of Clinical Pharmacology, University of Berne, Switzerland.
- Source
- Eur J Clin Invest, 1991 Feb, 21:1, 103-10
- Abstract
- Parenteral glutathione has therapeutic potential for targeted delivery of cysteine
equivalents. Thus, high doses of reduced glutathione (GSH) protect from the nephrotoxic
and urotoxic effects of cisplatinum and oxazaphosphorines. In order to elucidate the
underlying mechanisms the kinetics and the effect of glutathione on plasma and urine
sulphydryls were studied in 10 healthy volunteers. Following the intravenous infusion of 2
g m-2 of glutathione the concentration of total glutathione in plasma increased from 17.5
+/- 13.4 mumol l-1 (mean +/- SD) to 823 +/- 326 mumol l-1. The volume of distribution of
exogenous glutathione was 176 +/- 107 ml kg-1 and the elimination rate constant was 0.063
+/- 0.027 min-1 corresponding to a half-life of 14.1 +/- 9.2 min. Cysteine
in plasma increased from 8.9 +/- 3.5 mumol l-1 to 114 +/- 45 mumol l-1 after the infusion.
In spite of the increase in cysteine, the plasma concentration of total
cyst(e)ine (i.e. cysteine, cystine, and mixed disulphides) decreased,
suggesting an increased uptake of cysteine from plasma into cells.
Urinary excretion of glutathione and of cyst(e)ine was increased 300-fold and 10-fold,
respectively, in the 90 min following the infusion. The present data suggest that the
concentration of sulphydryls in the urinary tract and, more importantly, the intracellular
availability of cysteine increase markedly following parenteral
glutathione. The high intracellular concentration of cysteine may protect
against cisplatinum and oxazaphosphorine toxicity either directly or indirectly by
supporting the synthesis of glutathione.
- Language of Publication
- English
- Unique Identifier
- 91323361
- MeSH Heading (Major)
- Cysteine|*BL/UR; Cystine|*BL; Glutathione|*AD/PK
- MeSH Heading
- Adult; Cisplatin|AI/TO; Cystinuria|ET; Female; Human; Infusions, Intravenous; Male;
Middle Age; Support, Non-U.S. Gov't; Urinary Tract|DE
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-2972
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 15663-27-1 (Cisplatin); 24645-67-8 (Cystine); 4371-52-2 (Cysteine);
70-18-8 (Glutathione)
Record 47 from database: MEDLINE
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- Title
- Influence of combined use of selenious acid and SH compounds in parenteral preparations.
- Author
- Terada A; Yoshida M; Nakada M; Nakada K; Yamate N; Kobayashi T; Yoshida K
- Address
- Department of Pharmacy, St. Marianna University School of Medicine, Kawasaki, Japan.
- Source
- J Trace Elem Med Biol, 1997 Jun, 11:2, 105-9
- Abstract
- The influence of the combined use of selenious acid and SH compounds (glutathione (GSH)
and cysteine (Cys), or ascorbic acid (Asc)) on cultured venous vascular
cells was investigated experimentally. When cultured human umbilical venous vascular
endothelial cells were exposed to 10 microM of selenious acid combined with 0.5 mM-GSH or
0.5 mM-Cys, the release rates of [3H]-adenine and lactate dehydrogenase (LDH) from cells
into the medium increased significantly as compared with after exposure to selenious acid
alone, and damage to the vascular endothelial cells was found to be intensified. Addition
of 1 microM of selenious acid simultaneously with 0.5 mM-GSH or 0.5 mM-Cys showed no
differences in toxicity for the vascular endothelial cells as compared with the addition
of selenious acid alone. On the other hand, simultaneous exposure to 10 microM of
selenious acid and 1 mM-Asc induced no significant differences in the release rates of
[3H]-adenine and LDH, and no damage was observed to the vascular endothelial cells. These
results suggest that simultaneous addition of selenious acid together with GSH or Cys,
which have the SH-group, may cause damage to the vascular endothelial cells. Therefore
careful attention is warranted in total parenteral nutrition (TPN).
- Language of Publication
- English
- Unique Identifier
- 97431866
- MeSH Heading (Major)
- Ascorbic Acid|*AD/PD; Cysteine|*AD/PD; Endothelium, Vascular|CY/*DE;
Glutathione|*AD/PD; Parenteral Nutrition, Total|*; Selenium Compounds|*AD/PD
- MeSH Heading
- Cells, Cultured; Human
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0946-672X
- Country of Publication
- GERMANY
Record 48 from database: MEDLINE
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- Title
- Looking beneath the surface: the cell death pathway of Fas/APO-1 (CD95).
- Author
- Stanger BZ
- Address
- Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute,
Boston, Massachusetts 02115, USA.
- Source
- Mol Med, 1996 Jan, 2:1, 7-20
- Abstract
- SUMMARY: The biochemical basis of programmed cell death is poorly understood in mammals.
The cell surface receptor Fas/APO-1 (CD95) is one molecule known to be central to a number
of mammalian cell death processes. Several studies in the past year have led to insights
about the role of Fas/APO-1 in vivo and have also given some clues about the biochemical
components of the Fas/APO-1 death pathway. This article reviews those studies and discuss
models of Fas/APO-1 signaling and function. BACKGROUND: Cell death occurs as a normal
process in a wide variety of developmental and homeostatic contexts in metazoan organisms
(1); it represents the timely and appropriate fate for many or even the majority of cells
born in certain organ systems. Despite the importance and ubiquitous nature of such
physiologic, or "programmed", cell death, little is known about the molecular
events that mediate this process. That a conserved biochemical pathway exists is suggested
by the observation that programmed cell death is almost always accompanied by a consistent
set of morphologic changes, an appearance known as apoptosis (2). The identification of
the genes that control programmed cell death in higher eukaryotes has been hampered by
several inherent difficulties. First, the genetic tools so useful in dissecting cell death
pathways in Caenorhabditis elegans (3) and Drosophila (4) have not been available in
higher eukaryotes. Second, the death-inducing properties of such genes makes genetic
selection an impractical means of identification. Third, it appears that many cell death
genes are constitutively expressed and present in an inactive form (5), making it unlikely
that they could be discovered by techniques relying upon differential gene expression.
Finally, genes identified by virtue of an ability to induce death when overexpressed must
be subjected to rigorous criteria to determine whether the cell death is of physiologic
importance, since it is likely that overexpression of certain proteins may lead to toxic
effects that are distinct from the in vivo roles of those proteins. Two approaches to date
have yielded the most information about cell death processes: (i) identification of cell
death genes by classical genetic means coupled with characterization of their mammalian
homologs and (ii) screening for proteins capable of inducing cell death directly in
mammalian cells. The Fas antigen/APO-1 is an example of a protein discovered using the
latter approach, as it was first discovered as an inducer of cell death and later shown to
be necessary and sufficient for certain programmed deaths in vivo. More recent studies
have connected Fas to elements of cell death pathways in other species. It has been
proposed that Fas is related to the Drosophila cell death protein Reaper, and that in
signaling cell death Fas relies upon a relative of the C. elegans cell death protein
CED-3. Fas may therefore represent an evolutionarily conserved component of a universal
cell death pathway.
- Language of Publication
- English
- Unique Identifier
- 97056190
- MeSH Heading (Major)
- Antigens, CD95|*ME; Apoptosis|DE/*GE
- MeSH Heading
- Animal; Conserved Sequence|GE; Cysteine Proteinases|GE/ME; Evolution,
Molecular; Human; Mammals|ME/PH; Models, Genetic; Models, Molecular; Phosphoric Monoester
Hydrolases; Phosphotransferases; Sequence Homology; Signal Transduction
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1076-1551
- Country of Publication
- UNITED STATES
Record 49 from database: MEDLINE
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- Title
- Human rhinovirus 2A proteinase mutant and its second-site revertants.
- Author
- Luderer Gmach M; Liebig HD; Sommergruber W; Voss T; Fessl F; Skern T; Kuechler E
- Address
- Institut fÂur Biochemie der Universitaet Wien, Vienna, Austria.
- Source
- Biochem J, 1996 Aug, 318 ( Pt 1):, 213-8
- Abstract
- The 2A proteinases of human rhinoviruses are cysteine proteinases with
marked similarities to serine proteinases. In the absence of a three-dimensional
structure, we developed a genetical screening system for proteolytic activity and
identified Phe-130 as a key residue. The mutation Phe-130-->Tyr almost completely
inhibited enzyme activity at 37 degrees C; activity was, however, partially restored by
the following exchanges: Ser-27-->Pro, His-135-->Arg or His-137-->Arg. To
investigate this phenotypic reversion, 2A proteinases with the mutations Phe-130-->Tyr,
Phe-130-->Tyr/His-135-->Arg, Phe-130-->Tyr/His-137-->Arg, His-135-->Arg or
His-137-->Arg were expressed in Escherichia coli and purified. None of these mutations
affected the affinity of the enzyme for a peptide substrate. However, the
temperature-dependence of enzyme activity, as assayed by cleavage of a peptide substrate
and by monitoring the toxicity of the proteinases towards the E. coli strain BL21(DE3),
and the structural stability, as monitored by 8-anilino-I-naphthalenesulphonic acid
fluorescence and CD spectrometry, were affected. The thermal transition temperatures for
both the activity and the stability of the Phe-130-->Tyr 2A proteinase were reduced by
about 17 degrees C compared with the wild-type enzyme. The presence of the additional
mutations His-135-->Arg or His-137-->Arg in the Phe-130-->Tyr mutant increased
temperature stability by 3 degrees C and 6 degrees C respectively. Thus essential
interactions exist within the C-terminal domain of human rhinoviral 2A proteinases which
contribute to the overall stability and integrity of the enzyme.
- Language of Publication
- English
- Unique Identifier
- 96358508
- MeSH Heading (Major)
- Cysteine Proteinases|CH/*GE/*ME; Rhinovirus|*EN
- MeSH Heading
- Binding Sites; Circular Dichroism; Enzyme Stability; Escherichia coli|GE; Genes, Viral;
Genetic Screening; Human; Kinetics; Lac Operon; Mutagenesis, Site-Directed; Point
Mutation; Protein Denaturation; Recombinant Proteins|GE/ME; Support, Non-U.S. Gov't;
Temperature; Transformation, Genetic
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0264-6021
- Country of Publication
- ENGLAND
Record 50 from database: MEDLINE
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- Title
- Effect of selenium compounds and thiols on human mammary tumor cells.
- Author
- Yan L; Yee JA; Boylan LM; Spallholz JE
- Address
- Center for Food and Nutrition, Texas Tech University, Lubbock 79409.
- Source
- Biol Trace Elem Res, 1991 Aug, 30:2, 145-62
- Abstract
- The effect on cell viability and growth rate of sodium selenite, selenocystine, sodium
selenate, and selenomethionine at selenium concentrations of 6.25 and 12.5 uM was studied
in vitro on cells of the human mammary tumor cell line HTB123/DU4475. Selenite and
selenocystine affected both cell viability and growth rate of the tumor cells at these
selenium concentrations. Selenite and selenocystine decreased intracellular glutathione
concentrations, but did not affect tumor cell glutathione peroxidase activity. After six
days of exposure to either selenate or selenomethionine, the viability of tumor cells
remained stable, but cell growth, as measured by numbers of cells, was retarded. Neither
selenate nor selenomethionine produced changes in concentrations of intracellular
glutathione. The toxic effect of selenite on tumor cells was enhanced by addition of 0.25
mM glutathione to the growth medium. Preincubation of the tumor cells with 62.5 uM
buthionine sulfoximine decreased cellular glutathione to 15% of controls at 24 h and
enhanced the toxicity of selenite toward the tumor cells. Glutathione, 2-mercaptoethanol,
and L-cysteine were all toxic to the tumor cells in a dose-dependent
manner.
- Language of Publication
- English
- Unique Identifier
- 92153614
- MeSH Heading (Major)
- Breast Neoplasms|EN/*PA; Organoselenium Compounds|*PD; Selenium|*PD; Sulfhydryl
Compounds|*PD
- MeSH Heading
- Aged; Antimetabolites|PD; Cell Survival|DE; Cysteine|AA/PD; Female;
Glutathione|ME/PD; Glutathione Peroxidase|AI/ME; Human; Mercaptoethanol|PD; Methionine
Sulfoximine|AA/PD; Selenomethionine|PD; Support, Non-U.S. Gov't; Trypan Blue; Tumor Cells,
Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0163-4984
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 1.11.1.9 (Glutathione Peroxidase); 0 (Antimetabolites); 0 (Organoselenium Compounds);
0 (Sulfhydryl Compounds); 10102-18-8 (Sodium Selenite); 10236-58-5 (Selenocysteine);
13410-01-0 (sodium selenate); 1464-42-2 (Selenomethionine); 1982-67-8 (Methionine
Sulfoximine); 4371-52-2 (Cysteine); 5072-26-4 (Buthionine Sulfoximine);
60-24-2 (Mercaptoethanol); 70-18-8 (Glutathione); 72-57-1 (Trypan Blue); 7782-49-2
(Selenium); 7783-00-8 (selenious acid)
Record 51 from database: MEDLINE
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- Title
- D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation
status and HLA-DR3.
- Author
- Emery P; Panayi GS; Huston G; Welsh KI; Mitchell SC; Shah RR; Idle JR; Smith RL; Waring
RH
- Address
-
- Source
- J Rheumatol, 1984 Oct, 11:5, 626-32
- Abstract
- Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine,
displays a skewed distribution within a population. In 66 patients with rheumatoid
arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p
less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05),
appeared to be an independent risk factor of most importance in the group with extensive
sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or
impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of
RA patients was increased compared to that in a previous population study and requires
further investigation. Our findings explain a number of the toxic phenomena associated
with D-penicillamine administration in RA.
- Language of Publication
- English
- Unique Identifier
- 85082881
- MeSH Heading (Major)
- Arthritis, Rheumatoid|*DT/GE/ME; Carbocysteine|*ME; Cysteine|*AA;
Histocompatibility Antigens Class II|*GE; Penicillamine|*AE/ME/TU
- MeSH Heading
- Adult; Aged; Biotransformation; Female; Human; Male; Middle Age; Risk
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0315-162X
- Country of Publication
- CANADA
- CAS Registry/EC Number
- 0 (Histocompatibility Antigens Class II); 0 (HLA-DR3 Antigen); 0 (HLA-DR4 Antigen);
2387-59-9 (Carbocysteine); 4371-52-2 (Cysteine); 52-67-5 (Penicillamine)
Record 52 from database: MEDLINE
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- Title
- The influence of the protector thiol L-cystein on the toxic and therapeutic responses of
stabilized "activated" cyclophosphamide
(4-(S-ethanol)-sulfido-cyclophosphamide).
- Author
- Voelcker G; Laber P; Rockinger H; Wientzek C; Hohorst HJ
- Address
-
- Source
- Invest New Drugs, 1984, 2:2, 253-9
- Abstract
- The influence of L-cystein on the toxic and therapeutic responses of
4-(S-ethanol)-sulfido-cyclophosphamide (P1), a stabilized "activated"
cyclophosphamide, was investigated. Stabilized "activated" cyclophosphamides
hydrolyze under physiological conditions to 4-hydroxycyclophosphamide (4-OH-CP). The
antitumor activity of P1 was investigated on a heterotransplanted human bladder sarcoma in
nude mice and in perfusion experiments carried out on the isolated tumor bearing limb in
rats. Due to its rapid hydrolysis to 4-OH-CP, P1 exhibits severe local toxicity which is
decreased by the protector thiol L-cystein. Simultaneous application of double molar
amounts of L-cystein reduces toxicity in nude mice to approximately one-third. Therapeutic
activity is not affected by this ratio of L-cystein so that the protector thiol increases
the therapeutic efficacy of P1. Higher amounts of L-cystein reduce both the acute toxicity
in nude mice and the therapeutic efficacy against the human xenograft. The perfusion
experiments demonstrate that a P1 concentration necessary to cure rats with tumor bearing
limb is only tolerated in combination with L-cystein.
- Language of Publication
- English
- Unique Identifier
- 84288388
- MeSH Heading (Major)
- Bladder Neoplasms|*DT; Cyclophosphamide|*AA/AD/TO/TU; Sarcoma, Yoshida|*DT
- MeSH Heading
- Animal; Cysteine; Female; Human; Lethal Dose 50; Male; Mice; Mice,
Nude; Neoplasm Transplantation; Perfusion, Regional; Rats; Rats, Inbred Strains;
Structure-Activity Relationship; Support, Non-U.S. Gov't; Transplantation, Heterologous
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0167-6997
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 4371-52-2 (Cysteine); 50-18-0 (Cyclophosphamide); 88746-71-8 (Asta Z
7557)
Record 53 from database: MEDLINE
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- Title
- Neuronal nitric oxide synthase, a modular enzyme formed by convergent evolution:
structure studies of a cysteine thiolate-liganded heme protein that
hydroxylates L-arginine to produce NO. as a cellular signal [published erratum appears in
FASEB J 1996 Jul;10(9):1107]
- Author
- Masters BS; McMillan K; Sheta EA; Nishimura JS; Roman LJ; Martasek P
- Address
- Department of Biochemistry, University of Texas Health Science Center at San Antonio
78284-7760, USA.
- Source
- FASEB J, 1996 Apr, 10:5, 552-8
- Abstract
- The nitric oxide synthases (NOS-I, neuronal, NOS-II, inducible, and NOS-III,
endothelial) are the most recent additions to the large number of heme proteins that
contain cysteine thiolate-liganded protoporphyrin IX heme prosthetic
groups. This group of oxygenating enzymes also includes one of the largest gene families,
that of the cytochromes P450, which have been demonstrated to be involved in the
hydroxylation of a variety of substrates, including endogenous compounds (steroids, fatty
acids, and prostaglandins) and exogenous compounds (therapeutic drugs, environmental
toxicants, and carcinogens). The substrates for cytochromes P450 are universally
hydrophobic while the physiological substrate for the nitric oxide synthases is the amino
acid L-arginine, a hydrophilic compound. This review will discuss the approaches being
used to study the structure and mechanism of neuronal nitric oxide synthase in the context
of its known prosthetic groups and regulation by Ca(2+)-calmodulin and/or
tetrahydrobiopterin (BH4).
- Language of Publication
- English
- Unique Identifier
- 96210310
- MeSH Heading (Major)
- Arginine|*ME; Isoenzymes|*CH/ME; Neurons|*EN; Nitric Oxide|*ME; Nitric-Oxide
Synthase|*CH/ME
- MeSH Heading
- Animal; Cysteine|CH; Free Radicals; Hemeproteins|CH; Human;
Hydroxylation
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0892-6638
- Country of Publication
- UNITED STATES
Record 54 from database: MEDLINE
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- Title
- Interleukin-1beta secretion is impaired by inhibitors of the Atp binding cassette
transporter, ABC1.
- Author
- Hamon Y; Luciani MF; Becq F; Verrier B; Rubartelli A; Chimini G
- Address
- Centre d'Immunologie INSERM-CNRS de Marseille-Luminy, France.
- Source
- Blood, 1997 Oct, 90:8, 2911-5
- Abstract
- The production of interleukin-1beta (IL-1beta), a powerful mediator of inflammation, is
tightly regulated at several levels. However, in some pathologic conditions, a
pharmacologic treatment is required to control the toxicity of excessive extracellular
IL-1beta. Because of the heavy side effects of most therapies used in IL-1beta-mediated
pathologies, a goal of pharmacologic research is the development of selective
anti-IL-1beta drugs. We show here that the sulfonylurea glyburide, currently used in the
oral therapy of noninsulin dependent diabetes, is an inhibitor of IL-1beta secretion from
human monocytes and mouse macrophages. Glyburide reduces dramatically the recovery of
extracellular 17-kD IL-1beta in the absence of toxic effects on the cells and without
affecting the synthesis or processing of the IL-1beta precursor. IL-1beta belongs to the
family of leaderless secretory proteins released from the cell by a nonclassical secretory
route. In bacteria and yeast Atp binding cassette (ABC) transporters are involved in the
secretion of leaderless secretory proteins. Interestingly, glyburide blocks the anion
exchanger function of ABC1, a mammalian member of the family of ABC transporters. We thus
investigated the involvement of ABC1 in IL-1beta secretion, through the analysis of the
effects of drugs known to inhibit IL-1beta secretion, on the activity of ABC1 and in turn
the ability of known inhibitors of ABC1 of blocking IL-1beta secretion. Our data show that
IL-1beta secretion and the function of ABC1 as an anion exchanger are sensitive to the
same drugs, therefore suggesting an involvement of the ABC1 transporter in the secretion
of leaderless proteins in mammals.
- Language of Publication
- English
- Unique Identifier
- 98025873
- MeSH Heading (Major)
- Apoptosis|*; ABC Transporters|*AI; Glyburide|*PD; Glycoproteins|*AI; Interleukin-1|*SE
- MeSH Heading
- Acrylates|PD; Adenosine Triphosphate|PD; Animal; Anti-Inflammatory Agents,
Non-Steroidal|PD; Calcium Channel Blockers|PD; Cells, Cultured; Cysteine
Proteinases|ME; DIDS|PD; Human; Hypoglycemic Agents|PD; Indoles|PD;
Lipopolysaccharides|PD; Macrophages|DE/SE; Mice; Mice, Inbred CBA; Monocytes|DE/SE;
Recombinant Proteins|ME; Support, Non-U.S. Gov't; Verapamil|PD; Xenopus laevis
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-4971
- Country of Publication
- UNITED STATES
Record 55 from database: MEDLINE
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- Title
- Modulation of gene expression in subjects at risk for colorectal cancer by the
chemopreventive dithiolethione oltipraz.
- Author
- ODwyer PJ; Szarka CE; Yao KS; Halbherr TC; Pfeiffer GR; Green F; Gallo JM; Brennan J;
Frucht H; Goosenberg EB; Hamilton TC; Litwin S; Balshem AM; Engstrom PF; Clapper ML
- Address
- Fox Chase Cancer Center, Philadelpia, Pennsylvania 19111, USA.
- Source
- J Clin Invest, 1996 Sep, 98:5, 1210-7
- Abstract
- Prolonged exposure to mutagenic substances is strongly associated with an individual's
risk of developing colorectal cancer. Clinical investigation of oltipraz as a
chemopreventive agent is supported by its induction of the expression of detoxication
enzymes in various tissues, and its protective activity against the formation of
chemically induced colorectal tumors in animals. The goals of the present study were: to
determine if oltipraz could induce detoxicating gene expression in human tissues; to
identify effective non-toxic doses for more extensive clinical testing; and to establish a
relationship between effects in the colon mucosa and those in a more readily available
tissue, the peripheral mononuclear cell. 24 evaluable patients at high risk for colorectal
cancer were treated in a dose-finding study with oltipraz 125, 250, 500, or 1,000 mg/m2 as
a single oral dose. Biochemical analysis of sequential blood samples and colon mucosal
biopsies revealed increases in glutathione transferase activity at the lower dose levels.
These effects were not observed at the higher doses. More pronounced changes were observed
in detoxicating enzyme gene expression in both tissues at all doses. Peripheral
mononuclear cell and colon mRNA content for gamma-glutamylcysteine synthetase (gamma-GCS)
and DT-diaphorase increased after dosing to reach a peak on day 2-4 after treatment, and
declined to baseline in the subsequent 7-10 d. The extent of induction of gene expression
in colon mucosa reached a peak of 5.75-fold for gamma-GCS, and a peak of 4.14-fold for
DT-diaphorase at 250 mg/m2 ; higher doses were not more effective. Levels of gamma-GCS and
DT-diaphorase correlated closely (P < or = 0.001) between peripheral mononuclear cells
and colon mucosa both at baseline and at peak. These findings demonstrate that the
administration of minimally toxic agents at low doses may modulate the expression of
detoxicating genes in the tissues of individuals at high risk for cancer. Furthermore,
peripheral mononuclear cells may be used as a noninvasive surrogate endpoint biomarker for
the transcriptional response of normal colon mucosa to drug administration.
- Language of Publication
- English
- Unique Identifier
- 96379671
- MeSH Heading (Major)
- Anticarcinogenic Agents|*TU; Colorectal Neoplasms|*GE/*PC; Gene Expression Regulation,
Neoplastic|*; Pyrazines|*TU
- MeSH Heading
- Adult; Aged; Aged, 80 and over; Chemoprevention; Colon|DE/EN; Comparative Study; Female;
Glutamate-Cysteine Ligase|AN; Human; Intestinal Mucosa|DE/EN; Leukocytes,
Mononuclear|DE/EN; Male; Metabolic Detoxication, Drug; Middle Age; Mutagenesis|DE; NAD(P)H
Dehydrogenase (Quinone)|AN; Risk; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
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- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 0021-9738
- Country of Publication
- UNITED STATES
Record 56 from database: MEDLINE
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- Title
- High-dose intravenous glutathione in man. Pharmacokinetics and effects on cyst(e)ine in
plasma and urine.
- Author
- Aebi S; Assereto R; Lauterburg BH
- Address
- Department of Clinical Pharmacology, University of Berne, Switzerland.
- Source
- Eur J Clin Invest, 1991 Feb, 21:1, 103-10
- Abstract
Parenteral glutathione has therapeutic potential for targeted delivery
of cysteine equivalents. Thus, high doses of reduced glutathione (GSH)
protect from the nephrotoxic and urotoxic effects of cisplatinum and oxazaphosphorines. In
order to elucidate the underlying mechanisms the kinetics and the effect of glutathione on
plasma and urine sulphydryls were studied in 10 healthy volunteers. Following the
intravenous infusion of 2 g m-2 of glutathione the concentration of total glutathione in
plasma increased from 17.5 +/- 13.4 mumol l-1 (mean +/- SD) to 823 +/- 326 mumol l-1. The
volume of distribution of exogenous glutathione was 176 +/- 107 ml kg-1 and the
elimination rate constant was 0.063 +/- 0.027 min-1 corresponding to a half-life of 14.1
+/- 9.2 min. Cysteine in plasma increased from 8.9 +/- 3.5 mumol l-1 to
114 +/- 45 mumol l-1 after the infusion. In spite of the increase in cysteine,
the plasma concentration of total cyst(e)ine (i.e. cysteine, cystine, and
mixed disulphides) decreased, suggesting an increased uptake of cysteine
from plasma into cells. Urinary excretion of glutathione and of cyst(e)ine was increased
300-fold and 10-fold, respectively, in the 90 min following the infusion. The present data
suggest that the concentration of sulphydryls in the urinary tract and, more importantly,
the intracellular availability of cysteine increase markedly following
parenteral glutathione. The high intracellular concentration of cysteine
may protect against cisplatinum and oxazaphosphorine toxicity either directly or
indirectly by supporting the synthesis of glutathione.
- Language of Publication
- English
- Unique Identifier
- 91323361
- MeSH Heading (Major)
- Cysteine|*BL/UR; Cystine|*BL; Glutathione|*AD/PK
- MeSH Heading
- Adult; Cisplatin|AI/TO; Cystinuria|ET; Female; Human; Infusions, Intravenous; Male;
Middle Age; Support, Non-U.S. Gov't; Urinary Tract|DE
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-2972
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 15663-27-1 (Cisplatin); 24645-67-8 (Cystine); 4371-52-2 (Cysteine);
70-18-8 (Glutathione)
Record 57 from database: MEDLINE
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- Title
- Influence of combined use of selenious acid and SH compounds in parenteral preparations.
- Author
- Terada A; Yoshida M; Nakada M; Nakada K; Yamate N; Kobayashi T; Yoshida K
- Address
- Department of Pharmacy, St. Marianna University School of Medicine, Kawasaki, Japan.
- Source
- J Trace Elem Med Biol, 1997 Jun, 11:2, 105-9
- Abstract
- The influence of the combined use of selenious acid and SH compounds (glutathione (GSH)
and cysteine (Cys), or ascorbic acid (Asc)) on cultured venous vascular
cells was investigated experimentally. When cultured human umbilical venous vascular
endothelial cells were exposed to 10 microM of selenious acid combined with 0.5 mM-GSH or
0.5 mM-Cys, the release rates of [3H]-adenine and lactate dehydrogenase (LDH) from cells
into the medium increased significantly as compared with after exposure to selenious acid
alone, and damage to the vascular endothelial cells was found to be intensified. Addition
of 1 microM of selenious acid simultaneously with 0.5 mM-GSH or 0.5 mM-Cys showed no
differences in toxicity for the vascular endothelial cells as compared with the addition
of selenious acid alone. On the other hand, simultaneous exposure to 10 microM of
selenious acid and 1 mM-Asc induced no significant differences in the release rates of
[3H]-adenine and LDH, and no damage was observed to the vascular endothelial cells. These
results suggest that simultaneous addition of selenious acid together with GSH or Cys,
which have the SH-group, may cause damage to the vascular endothelial cells. Therefore
careful attention is warranted in total parenteral nutrition (TPN).
- Language of Publication
- English
- Unique Identifier
- 97431866
- MeSH Heading (Major)
- Ascorbic Acid|*AD/PD; Cysteine|*AD/PD; Endothelium, Vascular|CY/*DE;
Glutathione|*AD/PD; Parenteral Nutrition, Total|*; Selenium Compounds|*AD/PD
- MeSH Heading
- Cells, Cultured; Human
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0946-672X
- Country of Publication
- GERMANY
Record 58 from database: MEDLINE
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- Title
- S. cerevisiae and sulfur: a unique way to deal with the environment.
- Author
- Scheibel T; Bell S; Walke S
- Address
- Institut fÂur Biophysik und physikalische Biochemie, UniversitÂat Regensburg, Germany.
- Source
- FASEB J, 1997 Sep, 11:11, 917-21
- Abstract
- Saccharomyces cerevisiae is by far the best-studied unicellular eukaryote. Although
yeast cells are very similar to higher eukaryotes in many respects, there is striking
evidence that S. cerevisiae is not a perfect model for a eukaryotic cell (cf. 1). Here we
report that yeast proteins contain a significantly lower amount of cysteine
residues compared to other eukaryotes. Explanations for this phenomenon could not be found
in the sulfur metabolism of yeast, which showed no major differences from other organisms
(2-4). However, previous examinations could link a defect in sulfate uptake of S.
cerevisiae to an increased resistance against toxic substances like selenate and chromate
in the environment, which share the same permeases (5-7). This environmental problem might
have caused S. cerevisiae to down-regulate its sulfate uptake and therefore lead to a
lower amount of available sulfur in the cell, making it necessary to replace all
dispensable sulfur amino acids in proteins. We show in two examples that S. cerevisiae
proteins contain only such cysteine residues that are structurally or
functionally needed. Therefore, we conclude that S. cerevisiae has solved a widespread
environmental problem in a specific way which might be unique among eukaryotes.
- Language of Publication
- English
- Unique Identifier
- 97429852
- MeSH Heading (Major)
- Saccharomyces cerevisiae|*ME; Sulfur|*ME
- MeSH Heading
- Base Sequence; Cysteine|ME; Human; Methionine|ME; Molecular Sequence
Data; Superoxide Dismutase|CH
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0892-6638
- Country of Publication
- UNITED STATES
Record 59 from database: MEDLINE
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- Title
- S-phenylcysteine in albumin as a benzene biomarker.
- Author
- Bechtold WE; Strunk MR
- Address
- Inhalation Toxicology Research Institute, Albuquerque, New Mexico 87185, USA.
bbechtold@lucy.tli.org
- Source
- Environ Health Perspect, 1996 Dec, 104 Suppl 6:, 1147-9
- Abstract
- Biological markers of internal dose are useful for improving the extrapolation of health
effects from exposures to high levels of toxic air pollutants in animals to low, ambient
exposures in humans. Previous results from our laboratory have shown that benzene is
metabolized by humans to form the adduct S-phenylcysteine (SPC). Levels of SPC measured in
humans occupationally exposed to benzene were increased linearly relative to exposure
concentrations ranging from 0 to 23.1 ppm for 8 hr/day, 5 days/week. However, the method
of measurement used was laborious, prone to imprecision and interferences, and
insufficiently sensitive for the low-dose exposures anticipated in the United States (100
ppb >). An improved chemical method was necessary before SPC adducts in albumin could
be used as a benzene biomarker. A simple, sensitive method to measure SPC adducts is being
developed and is based on the cleavage of the cysteine sulfhydryl from
blood proteins treated with Raney nickel (RN) in deuterium oxide. The product of the
reaction with SPC is monodeuterobenzene. SPC treated with RN released monodeuterobenzene
in a concentration-dependent fashion. SPC was measured by RN treatment of globin from rats
repeatedly exposed by inhalation to 600 ppm benzene. SPC levels measured using the RN
approach were 690 +/- 390 pmol SPC/mg Hb (mean +/- % difference, n = 2), as opposed to 290
+/- 45 pmol SPC/mg Hb (mean +/- SEM, n = 3) as measured by our previous method. This
method may facilitate the cost-effective, routine analysis of SPC in large populations of
people exposed to ambient levels of benzene.
- Language of Publication
- English
- Unique Identifier
- 97147033
- MeSH Heading (Major)
- Benzene|*AN/*TO; Cysteine|*AA/BL; Serum Albumin|*CH
- MeSH Heading
- Air Pollutants, Environmental|AN/TO; Animal; Biological Markers|BL; Blood Chemical
Analysis|EC/MT/SN; Cost-Benefit Analysis; Environmental Exposure; Globin|CH; Human; Mass
Fragmentography; Nickel; Rats; Rats, Inbred F344; Sensitivity and Specificity
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0091-6765
- Country of Publication
- UNITED STATES
Record 60 from database: MEDLINE
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- Title
- Copper ions differ from other thiol reactive metal ions in their effects on the
concentration and redox status of thiols in HeLa cell cultures.
- Author
- Hultberg B; Andersson A; Isaksson A
- Address
- Department of Clinical Chemistry, University Hospital, Lund, Sweden.
- Source
- Toxicology, 1997 Feb, 117:2-3, 89-97
- Abstract
- Ions of metals such as copper, mercury, silver and cadmium are known to exhibit a high
affinity for thiol groups and may therefore severely disturb many metabolic functions in
the cell. Copper ions are also known to catalyse the formation of toxic oxygen species
through a series of redox reactions. In the present study, we have determined the
concentration of reduced and total glutathione, cysteine and homocysteine
in a cell culture system (HeLa cell line) after addition of these metal ions. The main
findings of the metal ion effect on the total thiol concentrations are that all metal ions
increased the release of glutathione into the medium. Since the intracellular
concentration of glutathione did not decrease under these conditions, the synthesis of
glutathione must have been increased. In contrast to the other metal ions, copper ions
also increased the release of homocysteine into the medium, possibly through interaction
with S-adenosylhomocysteine hydrolase. The main findings of metal ion effects on reduced
thiol are that, at concentrations not interfering with cell growth, mercury, silver and
cadmium ions increased the concentration of extracellular reduced glutathione, possibly
reflecting the increase of total glutathione in the medium. In contrast to the other metal
ions, the addition of even very low amounts of copper ions (1 mumol/l) decreased the
concentration of intra- and extracellular reduced thiols indicating oxidative stress.
- Language of Publication
- English
- Unique Identifier
- 97210824
- MeSH Heading (Major)
- Copper|*TO; Cysteine|*DE/ME; Glutathione|BI/*DE; Hela Cells|*DE/ME;
Homocysteine|*DE/ME; Metals, Heavy|*TO
- MeSH Heading
- Animal; Cadmium|TO; Cations|TO; Human; Mercury|TO; Oxidation-Reduction; Oxidative
Stress|DE; Silver|TO; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-483X
- Country of Publication
- IRELAND
Record 61 from database: MEDLINE
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- Title
- Cysteine concentrations in rodent tumors: unexpectedly high values may
cause therapy resistance.
- Author
- Koch CJ; Evans SM
- Address
- School of Medicine, Department of Radiation Oncology, University of Pennsylvania,
Philadelphia 19104-60721, USA.
- Source
- Int J Cancer, 1996 Sep, 67:5, 661-7
- Abstract
- Thiol-containing compounds of low m.w. play a key role in protecting cells from the
toxic effects of ionizing radiation, other free-radical-generating reactions, reactive
oxygen species and chemical toxins. Previous studies have emphasized the importance of the
tripeptide glutathione, which is the most abundant soluble thiol in cells. Cysteine
is more difficult to quantitate than glutathione, with reported concentrations only 1-10%
that of glutathione in most normal tissues and tissue culture cells. Using an
electrochemical method (oxidation of the functional -SH group) which allows the direct
assay of thiols after acid extraction of cells or tissue, our measurements confirm the
above indicated distribution of glutathione and cysteine in cells and
normal tissues. However, in several rat and mouse tumors grown in vivo, we found a much
higher proportion of cysteine, sometimes exceeding the millimolar
concentrations often found for glutathione. Our results have important implications for
predicting tumor radiation resistance since cysteine is a much better
radiation-protecting agent than glutathione. Since thiols and oxygen have interacting and
opposite effects on the net radiation response, high cysteine levels
would directly increase the proportion of radio-resistant cells in tumors.
- Language of Publication
- English
- Unique Identifier
- 96376783
- MeSH Heading (Major)
- Cysteine|*ME; Neoplasms, Experimental|*ME/*RT
- MeSH Heading
- Animal; Chromatography, High Pressure Liquid; Esophageal Neoplasms|ME; Female;
Glioma|ME; Glutathione|ME; Human; Liver Neoplasms, Experimental|ME; Male; Mammary
Neoplasms, Experimental|ME; Mice; Mice, Inbred C3H; Rats; Rats, Inbred BUF; Sarcoma,
Experimental|ME; Support, U.S. Gov't, P.H.S.; Treatment Outcome
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0020-7136
- Country of Publication
- UNITED STATES
Record 62 from database: MEDLINE
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- Title
- Protective action of ascorbic acid and sulfur compounds against acetaldehyde toxicity:
implications in alcoholism and smoking.
- Author
- Sprince H; Parker CM; Smith GG; Gonzales LJ
- Address
-
- Source
- Agents Actions, 1975 May, 5:2, 164-73
- Abstract
- Acetaldehyde is a toxic substance common to heavy drinking of alcohol and heavy smoking
of cigarettes. It has been implicated thereby in diseases of the cardiovascular,
respiratory, and central nervous systems. Protection against acetaldehyde toxicity (i.e.
anesthesia and lethality) was studied in rats by oral intubation of test compounds 30-45
minutes prior to oral intubation of a standardized oral LD 90 dose (18
millimoles/kilogram) of acetaldehyde. Animals were monitored for anesthesia (loss of
righting reflexes) and lethality for 72 hours. A total of 18 compounds was tested.
L-ascorbic acid at 2 millimoles/kilogram (mM/kg) showed moderate protection against
anesthesia and marked protection against lethality. Greatest protection against anesthesia
and lethality was obtained at 2 m M/kg with each of the following: L-cysteine,
N-acetyl-L-cysteine, thiamin-HCl, sodium metabisulfite, and L-cysteic acid. A combination
of L-ascorbic acid with L-cysteine, and thiamin-HCl at reduced dose
levels (2.0, 1.0 and 0.3 mM/kg, respectively) gave virtually complete protection. A
detailed literature review is presented of the rationale and significance of these
findings. Our findings could point the way to a possible build-up of natural protection
against the chronic body insult of acetaldehyde arising from heavy drinking of alcohol and
heavy smoking of cigarettes.
- Language of Publication
- English
- Unique Identifier
- 75222206
- MeSH Heading (Major)
- Acetaldehyde|ME/*TO; Ascorbic Acid|*PD; Sulfur|*PD
- MeSH Heading
- Acetylcysteine|PD; Alcoholism|CO; Anesthetics|PD; Animal; Cysteine|PD;
Human; Lethal Dose 50; Male; Rats; Smoking|CO; Support, U.S. Gov't, Non-P.H.S.;
Thiamine|PD
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0065-4299
- Country of Publication
- SWITZERLAND
Record 63 from database: MEDLINE
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- Title
- Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease.
- Author
- Lovell MA; Ehmann WD; Mattson MP; Markesbery WR
- Address
- Department of Chemistry, Sanders-Brown Center on Aging, University of Kentucky,
Lexington 40536-0230, USA.
- Source
- Neurobiol Aging, 1997 Sep, 18:5, 457-61
- Abstract
- 4-Hydroxynonenal (4-HNE), an aldehyde by-product of the peroxidation of fatty acids, has
been shown to have toxic properties for neurons in culture. In light of increasing
evidence that oxidative stress contributes to the neurodegenerative process in Alzheimer's
disease (AD), we quantified levels of free and protein-bound 4-HNE in the ventricular
fluid from 19 AD subjects and 13 control subjects by high-pressure liquid chromatography
and dot-blot immunoassay. Free 4-HNE levels were found to be significantly elevated in the
ventricular fluid of AD subjects compared with control subjects (p = 0.0096). These
results demonstrate increased lipid peroxidation in AD brain and suggest a role for 4-HNE
in the neurodegenerative process.
- Language of Publication
- English
- Unique Identifier
- 98051136
- MeSH Heading (Major)
- Aldehydes|CH/*ME; Alzheimer Disease|*ME; Body Fluids|*CH; Cerebral Ventricles|CH/*ME; Cysteine
Proteinase Inhibitors|CH/*ME
- MeSH Heading
- Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Female; Human; Lipid
Peroxidation; Male; Middle Age; Nerve Tissue Proteins|ME; Support, Non-U.S. Gov't;
Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0197-4580
- Country of Publication
- UNITED STATES
Record 64 from database: MEDLINE
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- Title
- Inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro.
Mediation by metabolism to N-D-lactoylcysteine and induction of apoptosis.
- Author
- Edwards LG; Adesida A; Thornalley PJ
- Address
- Department of Biological and Chemical Sciences, University of Essex, UK.
- Source
- Leuk Res, 1996 Jan, 20:1, 17-26
- Abstract
- The inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro is
mediated by the inhibtion of de novo pyridimine synthesis. When S-D-lactoylglutathione was
added to human leukaemia 60 cells in culture, it was hydrolysed by thiolesterase activity
to reduced glutathione and D-lactate but also converted to N-D-lactoylcysteinylglycine and
N-D-lactoylcysteine by gamma-glutamyl transferase and dipeptidase. The N-D-lactoylcysteine
inhibited human leukaemia 60 cell growth: the median growth inhibitory concentration
IC(50) value was 46.7 +/ -0.9 (N=30) and the median toxic concentration TC(50) value was
103 +/- 1 microM. Other N-(R)2-hydroxyacylcysteine derivatives, N-D-mandelylcysteine and
N-L-glyceroylcysteine, were less effective inhibitors of human leukaemia 60 cell growth,
whereas N-D-lactoylcysteine ethyl ester was more effective: the IC(50) value was 16.5 +/-
1.5 microM(N=8). Cytotoxic concentrations of S-D-lactoylglutathione-induced apoptosis in
human leukaemia 60 cells. The S-D-lactoylglutathione was not toxic to peripheral human
lymphocytes at the same concentrations but rather induced growth arrest. The expected
mechanism of action of N-D-lactoylcysteine is inhibition of dihydro-orotase, which is
particularly susceptible to inhibition by cysteine derivatives.
- Language of Publication
- English
- Unique Identifier
- 96226374
- MeSH Heading (Major)
- Antineoplastic Agents|*PD; Apoptosis|*/*DE; Cysteine|*PD;
Glutathione|*AA/PD; HL-60 Cells|*DE/ME/PA
- MeSH Heading
- Cell Division|DE; Human; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0145-2126
- Country of Publication
- ENGLAND
Record 65 from database: MEDLINE
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- Title
- The cell-damaging effects of low amounts of homocysteine and copper ions in human cell
line cultures are caused by oxidative stress.
- Author
- Hultberg B; Andersson A; Isaksson A
- Address
- Department of Clinical Chemistry, University Hospital, Lund, Sweden.
- Source
- Toxicology, 1997 Nov, 123:1-2, 33-40
- Abstract
- In the present study, we have investigated the increase of cell protein and the
concentration of glutathione, cysteine and homocysteine in cell culture
systems (HeLa cell line) after addition of low amounts (100-500 micromol/l) of
homocysteine and/or copper. The thiols and cell protein were determined in cell cultures
with daily additions of new medium with and without homocysteine and/or copper ions for 3
days. The present study shows that extracellularly added homocysteine (500 and 2000
micromol/l) resulted in signs of cell toxicity (decreased intracellular glutathione level
and/or retarded cell growth). After the addition of copper ions (10, 50 or 100
micromol/l), complex changes in the concentrations of thiols in cell cultures occurred but
cell growth was normal. After the addition of both homocysteine and copper ions, changes
similar to those seen with the addition of copper ions and homocysteine alone were noted.
However, synergistic features after addition of 500 micromol/l homocysteine and 10 or 50
micromol/l of copper ions were a significantly retarded cell growth and decreased
concentration of cellular glutathione. In HeLa cell lines with initial low cell density
and in an endothelial cell line (ECV 304), even the presence of 100 micromol/l of
homocysteine and 10 micromol/l of copper ions inhibited cell growth and decreased the
cellular level of glutathione. Whilst the level of homocysteine in our 3-day cell-culture
experiments is higher than the mild hyperhomocysteinemia thought to be atherogenic in
humans (20-30 micromol/l), it is conceivable that over a longer time course (several
decades), this mild hyperhomocysteinemia could be sufficient to induce cellular effects
similar to those found in the present study, eventually leading to atherosclerosis.
- Language of Publication
- English
- Unique Identifier
- 98006145
- MeSH Heading (Major)
- Copper|*TO; Homocysteine|ME/*TO; Oxidative Stress|*
- MeSH Heading
- Cations, Divalent; Cell Division|DE; Cell Line, Transformed; Cysteine|ME;
Endothelium|CY/ME; Glutathione|ME; Hela Cells; Human; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-483X
- Country of Publication
- IRELAND
Record 66 from database: MEDLINE
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- Title
- Amyotrophic lateral sclerosis: fasting plasma levels of cysteine and
inorganic sulfate are normal, as are brain contents of cysteine [see
comments]
- Author
- Perry TL; Krieger C; Hansen S; Tabatabaei A
- Address
- Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver,
Canada.
- Source
- Neurology, 1991 Apr, 41:4, 487-90
- Abstract
- Recent reports suggest that amyotrophic lateral sclerosis (ALS) is caused by one or more
unidentified neurotoxins that are poorly metabolized in patients to less toxic and more
readily excreted compounds, and that a genetically determined defect in cysteine
degradation and in inorganic sulfate production is the mechanism underlying a failure to
metabolize xenobiotics normally in ALS. We measured concentrations of total cysteine
and of inorganic sulfate in the plasma of age-matched groups of ALS patients and healthy
control subjects and found no differences. L-Cysteine, a putative
endogenous neurotoxin in ALS, was present in equal concentrations in autopsied brain from
ALS patients and controls.
- Language of Publication
- English
- Unique Identifier
- 91187204
- MeSH Heading (Major)
- Amyotrophic Lateral Sclerosis|BL/*ME; Brain|*ME; Cysteine|BL/*ME;
Sulfates|*BL
- MeSH Heading
- Adult; Aged; Aged, 80 and over; Fasting; Human; Middle Age; Reference Values; Support,
Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0028-3878
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Sulfates); 4371-52-2 (Cysteine)
Record 67 from database: MEDLINE
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- Title
- Ethanol decreases plasma sulphydryls in man: effect of disulfiram.
- Author
- Burgunder JM; Nelles J; Bilzer M; Lauterburg BH
- Address
- Department of Clinical Pharmacology, University of Berne, Switzerland.
- Source
- Eur J Clin Invest, 1988 Aug, 18:4, 420-4
- Abstract
- Based on animal experiments, interactions of ethanol and its metabolites with
sulphydryls have been implicated in the toxicity of ethanol, but acute effects of ethanol
on sulphydryls have not been documented in man. Plasma free glutathione and cysteine
were therefore measured following the administration of 0.2 g kg-1 ethanol to normal
healthy volunteers and chronic alcoholics on disulfiram, where the effects of high
concentrations of acetaldehyde can be observed. In both groups, plasma glutathione
decreased shortly following ethanol, and a sustained decreased in glutathione was seen in
the subjects on disulfiram. In patients on disulfiram, but not the healthy controls,
plasma cysteine decreased significantly. The decrease in plasma cysteine
was correlated to the rise in acetaldehyde, suggesting that cysteine, but
not glutathione, forms an adduct with acetaldehyde in man. We conclude that even moderate
doses of ethanol may disturb the sulphydryl homeostasis and could interfere with
biologically important processes that depend on sulphydryl groups.
- Language of Publication
- English
- Unique Identifier
- 89005304
- MeSH Heading (Major)
- Alcohol, Ethyl|*PD; Disulfiram|*PD; Sulfhydryl Compounds|*BL
- MeSH Heading
- Acetaldehyde|BL; Adult; Alcoholism|BL/DT; Cysteine|BL; Drug
Interactions; Female; Glutathione|BL; Human; Male; Middle Age; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-2972
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 0 (Sulfhydryl Compounds); 4371-52-2 (Cysteine); 64-17-5 (Alcohol,
Ethyl); 70-18-8 (Glutathione); 75-07-0 (Acetaldehyde); 97-77-8 (Disulfiram)
Record 68 from database: MEDLINE
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- Title
- Apoptotic cell death induced by serum and its prevention by thiols.
- Author
- Kurita T; Namiki H
- Address
- Department of Biology, School of Education, Waseda University, Tokyo, Japan.
- Source
- J Cell Physiol, 1994 Oct, 161:1, 63-70
- Abstract
- We recently reported that serum contains low molecular weight factors that inhibit
growth and cause cell death in vitro. The present study focused on identifying components
of basal media that counteract the toxic effects of serum. Amino acids L-cyst(e)ine and
L-tryptophan were found to prevent serum-induced cell death of TIG-1 human fetal lung
fibroblasts and other cell types. In addition to L-cysteine, other
thiol-bearing and dithiol-cleaving compounds showed a similar ability to rescue the cells.
Various inhibitors of protein or RNA synthesis also prevented the cell death. By contrast,
nonthiol-containing reducing agents and super oxide dismutase (SOD), an active
oxygen-eliminating enzyme, were ineffective. Thiol compounds appeared to exert a
supportive level in TIG-1 cells cultured in FBS, whereas protein synthesis inhibitors did
not alter the reduced intracellular thiol content. Fragmentation of DNA occurred prior to
the plasma membrane breakdown of dying cells. Taken together, these data suggest that
serum-induced cell death represents a form of apoptosis in which molecules containing
thiol groups are active participants.
- Language of Publication
- English
- Unique Identifier
- 95014762
- MeSH Heading (Major)
- Apoptosis|*DE/*PH; Blood|*PH; Blood Physiology|*; Sulfhydryl Compounds|*PD
- MeSH Heading
- Cell Line; Cysteine|PD; DNA Damage; Glutathione|AA/PD; Human;
Superoxide Dismutase|PD; Support, Non-U.S. Gov't; Tryptophan|PD
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0021-9541
- Country of Publication
- UNITED STATES
Record 69 from database: MEDLINE
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- Title
- Glutathione metabolism and its role in hepatotoxicity.
- Author
- DeLeve LD; Kaplowitz N
- Address
- University of Southern California, Division of Gastrointestinal and Liver Diseases, Los
Angeles.
- Source
- Pharmacol Ther, 1991 Dec, 52:3, 287-305
- Abstract
- Glutathione (GSH) fulfills several essential functions: Detoxification of free radicals
and toxic oxygen radicals, thiol-disulfide exchange and storage and transfer of cysteine.
GSH is present in all mammalian cells, but may be especially important for organs with
intense exposure to exogenous toxins such as the liver, kidney, lung and intestine. Within
the cell mitochondrial GSH is the main defense against physiological oxidant stress
generated by cellular respiration and may be a critical target for toxic oxygen and
electrophilic metabolites. Glutathione homeostasis is a highly complex process, which is
predominantly regulated by the liver, lung and kidney.
- Language of Publication
- English
- Unique Identifier
- 92319812
- MeSH Heading (Major)
- Glutathione|*/BI/ME/PH; Glutathione Transferases|*ME; Liver|*ME/PH
- MeSH Heading
- Animal; Cysteine|ME; Homeostasis; Human; Oxidation-Reduction; Support,
U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0163-7258
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- EC 2.5.1.18 (Glutathione Transferases); 4371-52-2 (Cysteine); 70-18-8
(Glutathione)
Record 70 from database: MEDLINE
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- Title
- Perchloroethylene-induced rat kidney tumors: an investigation of the mechanisms involved
and their relevance to humans.
- Author
- Green T; Odum J; Nash JA; Foster JR
- Address
- Imperial Chemical Industries plc, Central Toxicology Laboratory, Cheshire, Maclessfield,
United Kingdom.
- Source
- Toxicol Appl Pharmacol, 1990 Mar 15, 103:1, 77-89
- Abstract
- Lifetime exposure to perchloroethylene by inhalation has been shown to cause a low
incidence of renal tumors in male rats. The mechanisms responsible for the induction of
these tumors have been investigated following exposure of rats to perchloroethylene by
oral gavage (1500 mg/kg for up to 42 days) or by inhalation (400 ppm for 28 days).
Comparisons have been made between rats and mice in vivo and between rats, mice, and
humans in vitro. High doses of perchloroethylene given by gavage have been shown to be
toxic to the rat kidney, causing increases in urinary markers of kidney damage. A marked
accumulation of protein droplets (alpha-2u-globulin) was seen in the P2 segment of the
kidney proximal tubules. This response were not seen after inhalation exposure to 400 ppm
perchloroethylene for 28 days and hence may not be associated with the tumors seen at this
dose level. Protein droplet formation was seen after exposure to 1000 ppm
perchloroethylene, suggesting that 400 ppm is below the threshold dose required to induce
this response. Perchloroethylene has been shown to be metabolized by glutathione
conjugation in the liver, resulting in the formation of a mutagenic cysteine
conjugate which is activated by the kidney enzyme beta-lyase. Levels of the mercapturic
acid of perchloroethylene have been compared in rat and mouse urine. The enzyme kinetics
of hepatic glutathione conjugation and renal beta-lyase activation have been compared in
rat, mouse, and human tissues in vitro. Results of these studies are consistent with the
rat being the species susceptible to kidney tumors. Although human kidney was shown to
contain beta-lyase, glutathione conjugation of perchloroethylene could not be detected in
human liver. Perchloroethylene-induced male rat kidney tumors may be a result of chronic
toxicity, protein droplet nephropathy, and genotoxicity from the beta-lyase pathway. These
mechanisms appear to have little relevance to humans.
- Language of Publication
- English
- Unique Identifier
- 90194159
- MeSH Heading (Major)
- Kidney Neoplasms|*CI; Tetrachloroethylene|ME/*TO
- MeSH Heading
- gamma-Glutamyltransferase|PD; Administration, Inhalation; Animal; Cysteine|ME;
Cytochrome P-450|PH; Female; Glutathione|ME; Human; Kinetics; Male; Mice; Rats; Rats,
Inbred F344|RATS INBRED F 344; Risk
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0041-008X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 2.3.2.2 (gamma-Glutamyltransferase); 127-18-4 (Tetrachloroethylene); 4371-52-2 (Cysteine);
70-18-8 (Glutathione); 9035-51-2 (Cytochrome P-450)
Record 71 from database: MEDLINE
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- Title
- Inhibition of adenovirus infection with protease inhibitors.
- Author
- Sircar S; Keyvani Amineh H; Weber JM
- Address
- Department of Microbiology, Faculty of Medicine, University of Sherbrooke, Quebec,
Canada.
- Source
- Antiviral Res, 1996 May, 30:2-3, 147-53
- Abstract
- The effect of a series of cysteine and serine protease inhibitors was
tested on the growth of human adenovirus type 2 in tissue culture. In accordance with the
nature of the adenovirus protease, only the cysteine protease inhibitors
were effective in significantly reducing the production of infectious virus. Addition of
the inhibitors to the medium 18 h after infection gave IC50 of 30, 40 and 80 nM with
N-ethylmaleimide, leupeptin and E64c, respectively. Several lines of evidence suggest that
inhibition of infectious virus formation operated through the inhibition of the viral
protease rather than cellular toxicity: (a) the yield of physical particles declined only
4-5-fold, while that of infectious virus declined 3-7 orders of magnitude, (b) these
particles contained unprocessed precursor proteins and (c) pulse-chase experiments showed
that the inhibitors prevented the efficient processing of viral precursor proteins. We
conclude that the cysteine protease inhibitors efficiently depress the
formation of infectious adenovirus by inhibiting the viral protease.
- Language of Publication
- English
- Unique Identifier
- 96378031
- MeSH Heading (Major)
- Adenoviruses, Human|*DE; Antiviral Agents|*PD; Cysteine Proteinase
Inhibitors|*PD
- MeSH Heading
- Human; Support, Non-U.S. Gov't; Tumor Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0166-3542
- Country of Publication
- NETHERLANDS
Record 72 from database: MEDLINE
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- Title
- Augmentation of CD8 and CD4 lymphocytes subsets in AIDS infected children after
treatment with a non-toxic chelating agents compound--Rodilemid.
- Author
- Dinu R; Moraru I; State D; Dinu I
- Address
- Outhospital No. 1, Bucharest, Romania.
- Source
- Rom J Intern Med, 1995 Jul, 33:3-4, 205-10
- Abstract
- Twelve children were included into the protocol, 5 in March 1989 and 7 in April 1993.
All of them were HIV 1 positive and had diarrhoea, important adenopathy and opportunistic
infections. Seven out of 12 patients had an immunological monitoring. One out of 12
children with B hepatitis died with liver cirrhosis. Eleven children had a clear
improvement in their clinical course, during the treatment. Five out of 7 patients had a
significant increase of the CD4 lymphocytes at 4 and 7 months follow-up. Four patients had
an important and significant increase of the CD8 count at 4 months and 6 out of 7 patients
at 7 months. Interestingly, in 4 out of 7 patients after 7 months treatment we observed
higher than normal value of the CD8 count. Variations observed for CD8 population compared
to CD4 were more important.
- Language of Publication
- English
- Unique Identifier
- 96234866
- MeSH Heading (Major)
- Acquired Immunodeficiency Syndrome|*DT/*IM; Antiviral Agents|AE/*TU; Calcium
Gluconate|AE/*TU; Chelating Agents|AE/*TU; Cysteine|AE/*TU; CD4-CD8
Ratio|*DE; Edetic Acid|AE/*TU; HIV-1|*
- MeSH Heading
- AIDS-Related Opportunistic Infections|DT/IM; Child, Preschool; Drug Combinations; Human;
Infant; Time Factors
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 1220-4749
- Country of Publication
- ROMANIA
Record 73 from database: MEDLINE
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- Title
- Elevated 4-hydroxynonenal in ventricular fluid in Alzheimer's disease.
- Author
- Lovell MA; Ehmann WD; Mattson MP; Markesbery WR
- Address
- Department of Chemistry, Sanders-Brown Center on Aging, University of Kentucky,
Lexington 40536-0230, USA.
- Source
- Neurobiol Aging, 1997 Sep, 18:5, 457-61
- Abstract
- 4-Hydroxynonenal (4-HNE), an aldehyde by-product of the peroxidation of fatty acids, has
been shown to have toxic properties for neurons in culture. In light of increasing
evidence that oxidative stress contributes to the neurodegenerative process in Alzheimer's
disease (AD), we quantified levels of free and protein-bound 4-HNE in the ventricular
fluid from 19 AD subjects and 13 control subjects by high-pressure liquid chromatography
and dot-blot immunoassay. Free 4-HNE levels were found to be significantly elevated in the
ventricular fluid of AD subjects compared with control subjects (p = 0.0096). These
results demonstrate increased lipid peroxidation in AD brain and suggest a role for 4-HNE
in the neurodegenerative process.
- Language of Publication
- English
- Unique Identifier
- 98051136
- MeSH Heading (Major)
- Aldehydes|CH/*ME; Alzheimer Disease|*ME; Body Fluids|*CH; Cerebral Ventricles|CH/*ME; Cysteine
Proteinase Inhibitors|CH/*ME
- MeSH Heading
- Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Female; Human; Lipid
Peroxidation; Male; Middle Age; Nerve Tissue Proteins|ME; Support, Non-U.S. Gov't;
Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0197-4580
- Country of Publication
- UNITED STATES
Record 74 from database: MEDLINE
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- Title
- Inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro.
Mediation by metabolism to N-D-lactoylcysteine and induction of apoptosis.
- Author
- Edwards LG; Adesida A; Thornalley PJ
- Address
- Department of Biological and Chemical Sciences, University of Essex, UK.
- Source
- Leuk Res, 1996 Jan, 20:1, 17-26
- Abstract
- The inhibition of human leukaemia 60 cell growth by S-D-lactoylglutathione in vitro is
mediated by the inhibtion of de novo pyridimine synthesis. When S-D-lactoylglutathione was
added to human leukaemia 60 cells in culture, it was hydrolysed by thiolesterase activity
to reduced glutathione and D-lactate but also converted to N-D-lactoylcysteinylglycine and
N-D-lactoylcysteine by gamma-glutamyl transferase and dipeptidase. The N-D-lactoylcysteine
inhibited human leukaemia 60 cell growth: the median growth inhibitory concentration
IC(50) value was 46.7 +/ -0.9 (N=30) and the median toxic concentration TC(50) value was
103 +/- 1 microM. Other N-(R)2-hydroxyacylcysteine derivatives, N-D-mandelylcysteine and
N-L-glyceroylcysteine, were less effective inhibitors of human leukaemia 60 cell growth,
whereas N-D-lactoylcysteine ethyl ester was more effective: the IC(50) value was 16.5 +/-
1.5 microM(N=8). Cytotoxic concentrations of S-D-lactoylglutathione-induced apoptosis in
human leukaemia 60 cells. The S-D-lactoylglutathione was not toxic to peripheral human
lymphocytes at the same concentrations but rather induced growth arrest. The expected
mechanism of action of N-D-lactoylcysteine is inhibition of dihydro-orotase, which is
particularly susceptible to inhibition by cysteine derivatives.
- Language of Publication
- English
- Unique Identifier
- 96226374
- MeSH Heading (Major)
- Antineoplastic Agents|*PD; Apoptosis|*/*DE; Cysteine|*PD;
Glutathione|*AA/PD; HL-60 Cells|*DE/ME/PA
- MeSH Heading
- Cell Division|DE; Human; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0145-2126
- Country of Publication
- ENGLAND
Record 75 from database: MEDLINE
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- Title
- The cell-damaging effects of low amounts of homocysteine and copper ions in human cell
line cultures are caused by oxidative stress.
- Author
- Hultberg B; Andersson A; Isaksson A
- Address
- Department of Clinical Chemistry, University Hospital, Lund, Sweden.
- Source
- Toxicology, 1997 Nov, 123:1-2, 33-40
- Abstract
- In the present study, we have investigated the increase of cell protein and the
concentration of glutathione, cysteine and homocysteine in cell culture
systems (HeLa cell line) after addition of low amounts (100-500 micromol/l) of
homocysteine and/or copper. The thiols and cell protein were determined in cell cultures
with daily additions of new medium with and without homocysteine and/or copper ions for 3
days. The present study shows that extracellularly added homocysteine (500 and 2000
micromol/l) resulted in signs of cell toxicity (decreased intracellular glutathione level
and/or retarded cell growth). After the addition of copper ions (10, 50 or 100
micromol/l), complex changes in the concentrations of thiols in cell cultures occurred but
cell growth was normal. After the addition of both homocysteine and copper ions, changes
similar to those seen with the addition of copper ions and homocysteine alone were noted.
However, synergistic features after addition of 500 micromol/l homocysteine and 10 or 50
micromol/l of copper ions were a significantly retarded cell growth and decreased
concentration of cellular glutathione. In HeLa cell lines with initial low cell density
and in an endothelial cell line (ECV 304), even the presence of 100 micromol/l of
homocysteine and 10 micromol/l of copper ions inhibited cell growth and decreased the
cellular level of glutathione. Whilst the level of homocysteine in our 3-day cell-culture
experiments is higher than the mild hyperhomocysteinemia thought to be atherogenic in
humans (20-30 micromol/l), it is conceivable that over a longer time course (several
decades), this mild hyperhomocysteinemia could be sufficient to induce cellular effects
similar to those found in the present study, eventually leading to atherosclerosis.
- Language of Publication
- English
- Unique Identifier
- 98006145
- MeSH Heading (Major)
- Copper|*TO; Homocysteine|ME/*TO; Oxidative Stress|*
- MeSH Heading
- Cations, Divalent; Cell Division|DE; Cell Line, Transformed; Cysteine|ME;
Endothelium|CY/ME; Glutathione|ME; Hela Cells; Human; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-483X
- Country of Publication
- IRELAND
Record 76 from database: MEDLINE
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- Title
- Amyotrophic lateral sclerosis: fasting plasma levels of cysteine and
inorganic sulfate are normal, as are brain contents of cysteine [see
comments]
- Author
- Perry TL; Krieger C; Hansen S; Tabatabaei A
- Address
- Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver,
Canada.
- Source
- Neurology, 1991 Apr, 41:4, 487-90
- Abstract
- Recent reports suggest that amyotrophic lateral sclerosis (ALS) is caused by one or more
unidentified neurotoxins that are poorly metabolized in patients to less toxic and more
readily excreted compounds, and that a genetically determined defect in cysteine
degradation and in inorganic sulfate production is the mechanism underlying a failure to
metabolize xenobiotics normally in ALS. We measured concentrations of total cysteine
and of inorganic sulfate in the plasma of age-matched groups of ALS patients and healthy
control subjects and found no differences. L-Cysteine, a putative
endogenous neurotoxin in ALS, was present in equal concentrations in autopsied brain from
ALS patients and controls.
- Language of Publication
- English
- Unique Identifier
- 91187204
- MeSH Heading (Major)
- Amyotrophic Lateral Sclerosis|BL/*ME; Brain|*ME; Cysteine|BL/*ME;
Sulfates|*BL
- MeSH Heading
- Adult; Aged; Aged, 80 and over; Fasting; Human; Middle Age; Reference Values; Support,
Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0028-3878
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Sulfates); 4371-52-2 (Cysteine)
Record 77 from database: MEDLINE
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- Title
- Ethanol decreases plasma sulphydryls in man: effect of disulfiram.
- Author
- Burgunder JM; Nelles J; Bilzer M; Lauterburg BH
- Address
- Department of Clinical Pharmacology, University of Berne, Switzerland.
- Source
- Eur J Clin Invest, 1988 Aug, 18:4, 420-4
- Abstract
- Based on animal experiments, interactions of ethanol and its metabolites with
sulphydryls have been implicated in the toxicity of ethanol, but acute effects of ethanol
on sulphydryls have not been documented in man. Plasma free glutathione and cysteine
were therefore measured following the administration of 0.2 g kg-1 ethanol to normal
healthy volunteers and chronic alcoholics on disulfiram, where the effects of high
concentrations of acetaldehyde can be observed. In both groups, plasma glutathione
decreased shortly following ethanol, and a sustained decreased in glutathione was seen in
the subjects on disulfiram. In patients on disulfiram, but not the healthy controls,
plasma cysteine decreased significantly. The decrease in plasma cysteine
was correlated to the rise in acetaldehyde, suggesting that cysteine, but
not glutathione, forms an adduct with acetaldehyde in man. We conclude that even moderate
doses of ethanol may disturb the sulphydryl homeostasis and could interfere with
biologically important processes that depend on sulphydryl groups.
- Language of Publication
- English
- Unique Identifier
- 89005304
- MeSH Heading (Major)
- Alcohol, Ethyl|*PD; Disulfiram|*PD; Sulfhydryl Compounds|*BL
- MeSH Heading
- Acetaldehyde|BL; Adult; Alcoholism|BL/DT; Cysteine|BL; Drug
Interactions; Female; Glutathione|BL; Human; Male; Middle Age; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-2972
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 0 (Sulfhydryl Compounds); 4371-52-2 (Cysteine); 64-17-5 (Alcohol,
Ethyl); 70-18-8 (Glutathione); 75-07-0 (Acetaldehyde); 97-77-8 (Disulfiram)
Record 78 from database: MEDLINE
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- Title
- Apoptotic cell death induced by serum and its prevention by thiols.
- Author
- Kurita T; Namiki H
- Address
- Department of Biology, School of Education, Waseda University, Tokyo, Japan.
- Source
- J Cell Physiol, 1994 Oct, 161:1, 63-70
- Abstract
- We recently reported that serum contains low molecular weight factors that inhibit
growth and cause cell death in vitro. The present study focused on identifying components
of basal media that counteract the toxic effects of serum. Amino acids L-cyst(e)ine and
L-tryptophan were found to prevent serum-induced cell death of TIG-1 human fetal lung
fibroblasts and other cell types. In addition to L-cysteine, other
thiol-bearing and dithiol-cleaving compounds showed a similar ability to rescue the cells.
Various inhibitors of protein or RNA synthesis also prevented the cell death. By contrast,
nonthiol-containing reducing agents and super oxide dismutase (SOD), an active
oxygen-eliminating enzyme, were ineffective. Thiol compounds appeared to exert a
supportive level in TIG-1 cells cultured in FBS, whereas protein synthesis inhibitors did
not alter the reduced intracellular thiol content. Fragmentation of DNA occurred prior to
the plasma membrane breakdown of dying cells. Taken together, these data suggest that
serum-induced cell death represents a form of apoptosis in which molecules containing
thiol groups are active participants.
- Language of Publication
- English
- Unique Identifier
- 95014762
- MeSH Heading (Major)
- Apoptosis|*DE/*PH; Blood|*PH; Blood Physiology|*; Sulfhydryl Compounds|*PD
- MeSH Heading
- Cell Line; Cysteine|PD; DNA Damage; Glutathione|AA/PD; Human;
Superoxide Dismutase|PD; Support, Non-U.S. Gov't; Tryptophan|PD
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0021-9541
- Country of Publication
- UNITED STATES
Record 79 from database: MEDLINE
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- Title
- Glutathione metabolism and its role in hepatotoxicity.
- Author
- DeLeve LD; Kaplowitz N
- Address
- University of Southern California, Division of Gastrointestinal and Liver Diseases, Los
Angeles.
- Source
- Pharmacol Ther, 1991 Dec, 52:3, 287-305
- Abstract
- Glutathione (GSH) fulfills several essential functions: Detoxification of free radicals
and toxic oxygen radicals, thiol-disulfide exchange and storage and transfer of cysteine.
GSH is present in all mammalian cells, but may be especially important for organs with
intense exposure to exogenous toxins such as the liver, kidney, lung and intestine. Within
the cell mitochondrial GSH is the main defense against physiological oxidant stress
generated by cellular respiration and may be a critical target for toxic oxygen and
electrophilic metabolites. Glutathione homeostasis is a highly complex process, which is
predominantly regulated by the liver, lung and kidney.
- Language of Publication
- English
- Unique Identifier
- 92319812
- MeSH Heading (Major)
- Glutathione|*/BI/ME/PH; Glutathione Transferases|*ME; Liver|*ME/PH
- MeSH Heading
- Animal; Cysteine|ME; Homeostasis; Human; Oxidation-Reduction; Support,
U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0163-7258
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- EC 2.5.1.18 (Glutathione Transferases); 4371-52-2 (Cysteine); 70-18-8
(Glutathione)
Record 80 from database: MEDLINE
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- Title
- Perchloroethylene-induced rat kidney tumors: an investigation of the mechanisms involved
and their relevance to humans.
- Author
- Green T; Odum J; Nash JA; Foster JR
- Address
- Imperial Chemical Industries plc, Central Toxicology Laboratory, Cheshire, Maclessfield,
United Kingdom.
- Source
- Toxicol Appl Pharmacol, 1990 Mar 15, 103:1, 77-89
- Abstract
- Lifetime exposure to perchloroethylene by inhalation has been shown to cause a low
incidence of renal tumors in male rats. The mechanisms responsible for the induction of
these tumors have been investigated following exposure of rats to perchloroethylene by
oral gavage (1500 mg/kg for up to 42 days) or by inhalation (400 ppm for 28 days).
Comparisons have been made between rats and mice in vivo and between rats, mice, and
humans in vitro. High doses of perchloroethylene given by gavage have been shown to be
toxic to the rat kidney, causing increases in urinary markers of kidney damage. A marked
accumulation of protein droplets (alpha-2u-globulin) was seen in the P2 segment of the
kidney proximal tubules. This response were not seen after inhalation exposure to 400 ppm
perchloroethylene for 28 days and hence may not be associated with the tumors seen at this
dose level. Protein droplet formation was seen after exposure to 1000 ppm
perchloroethylene, suggesting that 400 ppm is below the threshold dose required to induce
this response. Perchloroethylene has been shown to be metabolized by glutathione
conjugation in the liver, resulting in the formation of a mutagenic cysteine
conjugate which is activated by the kidney enzyme beta-lyase. Levels of the mercapturic
acid of perchloroethylene have been compared in rat and mouse urine. The enzyme kinetics
of hepatic glutathione conjugation and renal beta-lyase activation have been compared in
rat, mouse, and human tissues in vitro. Results of these studies are consistent with the
rat being the species susceptible to kidney tumors. Although human kidney was shown to
contain beta-lyase, glutathione conjugation of perchloroethylene could not be detected in
human liver. Perchloroethylene-induced male rat kidney tumors may be a result of chronic
toxicity, protein droplet nephropathy, and genotoxicity from the beta-lyase pathway. These
mechanisms appear to have little relevance to humans.
- Language of Publication
- English
- Unique Identifier
- 90194159
- MeSH Heading (Major)
- Kidney Neoplasms|*CI; Tetrachloroethylene|ME/*TO
- MeSH Heading
- gamma-Glutamyltransferase|PD; Administration, Inhalation; Animal; Cysteine|ME;
Cytochrome P-450|PH; Female; Glutathione|ME; Human; Kinetics; Male; Mice; Rats; Rats,
Inbred F344|RATS INBRED F 344; Risk
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0041-008X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 2.3.2.2 (gamma-Glutamyltransferase); 127-18-4 (Tetrachloroethylene); 4371-52-2 (Cysteine);
70-18-8 (Glutathione); 9035-51-2 (Cytochrome P-450)
Record 81 from database: MEDLINE
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- Title
- Inhibition of adenovirus infection with protease inhibitors.
- Author
- Sircar S; Keyvani Amineh H; Weber JM
- Address
- Department of Microbiology, Faculty of Medicine, University of Sherbrooke, Quebec,
Canada.
- Source
- Antiviral Res, 1996 May, 30:2-3, 147-53
- Abstract
- The effect of a series of cysteine and serine protease inhibitors was
tested on the growth of human adenovirus type 2 in tissue culture. In accordance with the
nature of the adenovirus protease, only the cysteine protease inhibitors
were effective in significantly reducing the production of infectious virus. Addition of
the inhibitors to the medium 18 h after infection gave IC50 of 30, 40 and 80 nM with
N-ethylmaleimide, leupeptin and E64c, respectively. Several lines of evidence suggest that
inhibition of infectious virus formation operated through the inhibition of the viral
protease rather than cellular toxicity: (a) the yield of physical particles declined only
4-5-fold, while that of infectious virus declined 3-7 orders of magnitude, (b) these
particles contained unprocessed precursor proteins and (c) pulse-chase experiments showed
that the inhibitors prevented the efficient processing of viral precursor proteins. We
conclude that the cysteine protease inhibitors efficiently depress the
formation of infectious adenovirus by inhibiting the viral protease.
- Language of Publication
- English
- Unique Identifier
- 96378031
- MeSH Heading (Major)
- Adenoviruses, Human|*DE; Antiviral Agents|*PD; Cysteine Proteinase
Inhibitors|*PD
- MeSH Heading
- Human; Support, Non-U.S. Gov't; Tumor Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0166-3542
- Country of Publication
- NETHERLANDS
Record 82 from database: MEDLINE
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- Title
- Augmentation of CD8 and CD4 lymphocytes subsets in AIDS infected children after
treatment with a non-toxic chelating agents compound--Rodilemid.
- Author
- Dinu R; Moraru I; State D; Dinu I
- Address
- Outhospital No. 1, Bucharest, Romania.
- Source
- Rom J Intern Med, 1995 Jul, 33:3-4, 205-10
- Abstract
- Twelve children were included into the protocol, 5 in March 1989 and 7 in April 1993.
All of them were HIV 1 positive and had diarrhoea, important adenopathy and opportunistic
infections. Seven out of 12 patients had an immunological monitoring. One out of 12
children with B hepatitis died with liver cirrhosis. Eleven children had a clear
improvement in their clinical course, during the treatment. Five out of 7 patients had a
significant increase of the CD4 lymphocytes at 4 and 7 months follow-up. Four patients had
an important and significant increase of the CD8 count at 4 months and 6 out of 7 patients
at 7 months. Interestingly, in 4 out of 7 patients after 7 months treatment we observed
higher than normal value of the CD8 count. Variations observed for CD8 population compared
to CD4 were more important.
- Language of Publication
- English
- Unique Identifier
- 96234866
- MeSH Heading (Major)
- Acquired Immunodeficiency Syndrome|*DT/*IM; Antiviral Agents|AE/*TU; Calcium
Gluconate|AE/*TU; Chelating Agents|AE/*TU; Cysteine|AE/*TU; CD4-CD8
Ratio|*DE; Edetic Acid|AE/*TU; HIV-1|*
- MeSH Heading
- AIDS-Related Opportunistic Infections|DT/IM; Child, Preschool; Drug Combinations; Human;
Infant; Time Factors
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 1220-4749
- Country of Publication
- ROMANIA
Record 83 from database: MEDLINE
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- Title
- Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen.
- Author
- Kurokawa Y; Maekawa A; Takahashi M; Hayashi Y
- Address
- Division of Toxicology, National Institute of Hygienic Sciences, Tokyo, Japan.
- Source
- Environ Health Perspect, 1990 Jul, 87:, 309-35
- Abstract
- Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive,
mainly in the bread-making process. Although adverse effects are not evident in animals
fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in
rats and nephrotoxic in both man and experimental animals when given orally. It has been
demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and
follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the
mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing
both initiating and promoting activities for rat renal tumorigenesis. However, the
potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic
activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome
aberrations both in vitro and in vivo. Glutathione and cysteine degrade
KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation
in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its
toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine
in the rat kidney. A wide range of data from applications of various analytical methods
are now available for risk assessment purposes.
- Language of Publication
- English
- Unique Identifier
- 91099248
- MeSH Heading (Major)
- Bread|*/AN; Bromates|AE/PK/PO/*TO; Carcinogens|PK/*TO; Carcinoma, Renal Cell|*CI; Food
Additives|AE/*TO; Hair Preparations|*PO; Kidney Neoplasms|*CI
- MeSH Heading
- Adenocarcinoma|CI; Administration, Oral; Animal; Bromides|AN/TO; Carcinogenicity Tests;
Chromosome Aberrations; Cocarcinogenesis; Comparative Study; Cysteine|ME;
Dose-Response Relationship, Drug; Fish Products; Food Handling; Glutathione|ME; Great
Britain; Hamsters; Hearing Loss, Partial|CI; Human; Japan|EP; Kidney Diseases|CI; Maximum
Permissible Exposure Level; Mesocricetus; Mesothelioma|CI; Mice; Mutagenicity Tests;
Occupational Diseases|CI/EP; Peritoneal Neoplasms|CI; Potassium|AN/TO; Rats; Rats, Inbred
F344|RATS INBRED F 344; Species Specificity; Support, Non-U.S. Gov't; Thyroid
Neoplasms|CI; United States|EP
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0091-6765
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Bromates); 0 (Bromides); 0 (Carcinogens); 0 (Food Additives); 0 (Hair Preparations);
4371-52-2 (Cysteine); 70-18-8 (Glutathione); 7440-09-7 (Potassium);
7758-01-2 (potassium bromate); 7758-02-3 (potassium bromide)
Record 84 from database: MEDLINE
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- Title
- Cystinotic and normal fibroblasts: differential susceptibility to cysteine
toxicity in vitro.
- Author
- Orloff S; Mukherjee AB; Butler JD; Foley B; Schulman JD
- Address
-
- Source
- In Vitro, 1980 Aug, 16:8, 655-60
- Abstract
- Extracellular cysteine concentrations between 0.5 and 2.5 mM resulted
in death of normal but not cystinotic cells grown in Eagle's minimal essential medium
containing supplemental fetal bovine serum and antibiotics. Differential cell survival was
determined by viable cell counting using Trypan Blue dye exclusion. In cocultivation
experiments of [3H]thymidine-labelled cystinotic fibroblasts with nonradioactive normal
fibroblasts, autoradiography confirmed the selective survival of cystinotic cells in
medium containing 1 mM cysteine. At this concentration of 1 mM cysteine,
intracellular cystine content increased slightly in surviving normal cells but not in
cystinotic cells, which normally contain a high level of intracellular cystine. This
comparative resistance of cystinotic fibroblasts to elevated extracellular cysteine
concentrations forms the basis for an in vitro selective system for these mutant human
cells. Further exploration of this resistance phenomenon may well expand the understanding
of the molecular defect in cystinotic cells.
- Language of Publication
- English
- Unique Identifier
- 81025475
- MeSH Heading (Major)
- Cysteine|*TO; Cystinosis|*PA
- MeSH Heading
- Cell Count; Cell Line; Cell Survival|DE; Child; Comparative Study; Fibroblasts|DE; Human
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0073-5655
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 4371-52-2 (Cysteine)
Record 85 from database: MEDLINE
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- Title
- Plasmodium falciparum: effects of proteinase inhibitors on globin hydrolysis by cultured
malaria parasites.
- Author
- Rosenthal PJ
- Address
- Department of Medicine, San Francisco General Hospital, California.
- Source
- Exp Parasitol, 1995 Mar, 80:2, 272-81
- Abstract
- The effects of peptide proteinase inhibitors on globin hydrolysis by cultured malaria
parasites were studied. All of the four cysteine proteinase inhibitors
evaluated blocked globin hydrolysis, as documented by the development of a morphological
abnormality in which parasite food vacuoles filled with undegraded globin and by SDS-PAGE
showing that the cysteine proteinase inhibitor-treated parasites
accumulated large quantities of globin. The aspartic proteinase inhibitor pepstatin did
not block globin hydrolysis by cultured parasites. None of seven antimalarial drugs tested
elicited the food vacuole abnormality caused by cysteine proteinase
inhibitors, indicating that this morphological alteration was not simply a sign of
nonspecific parasite toxicity. Our results indicate that a trophozoite cysteine
proteinase is required for initial cleavages of globin by intact malaria parasites.
- Language of Publication
- English
- Unique Identifier
- 95203410
- MeSH Heading (Major)
- Cysteine Proteinase Inhibitors|*PD; Erythrocytes|ME/*PS; Globin|*ME;
Plasmodium falciparum|*DE/ME/UL
- MeSH Heading
- Animal; Antimalarials|PD; Chymotrypsin|AI; Comparative Study; Coumarins|ME;
Dipeptides|ME/PD; Electrophoresis, Polyacrylamide Gel; Fluorescent Dyes|ME; Human;
Hydrolysis|DE; Leucine|AA/PD; Leupeptins|PD; Oligopeptides|PD; Pepstatins|PD; Support,
Non-U.S. Gov't; Vacuoles|DE/ME
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-4894
- Country of Publication
- UNITED STATES
Record 86 from database: MEDLINE
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- Title
- L-Homocysteic acid as an alternative cytotoxin for studying glutamate-induced cellular
degeneration of Huntington's disease and normal skin fibroblasts.
- Author
- May PC; Gray PN
- Address
-
- Source
- Life Sci, 1985 Oct 21, 37:16, 1483-9
- Abstract
- Huntington's Disease (HD) and normal skin fibroblasts in culture were exposed to several
acidic amino acids structurally related to L-glutamate which have excitotoxic properties
in the nervous system. L-Homocysteic acid, a sulfonic acid analogue of glutamate, was the
only other acidic amino acid causing fibroblast degeneration similar to that induced by
glutamate. None of the other compounds tested, including the D isomer of homocysteic acid,
were as toxic as 30 mM glutamate. As previously noted with glutamate treatment, HD
fibroblasts demonstrated an increased sensitivity to L-homocysteic acid compared to
controls. In contrast to glutamate, no cellular metabolism of L-homocysteic acid could be
detected; a property which may account for the increased cytotoxicity of L-homocysteic
acid compared to glutamate. The identification of L-homocysteic acid, a glutamate analogue
which undergoes limited metabolism, should enable the elucidation of the toxic mechanism
of glutamate and facilitate the determination of the site conferring increased sensitivity
of cultured HD fibroblasts to glutamate.
- Language of Publication
- English
- Unique Identifier
- 86013357
- MeSH Heading (Major)
- Glutamates|ME/*TO; Homocysteine|*AA/ME/TO; Huntington's Disease|*PA; Skin|CY/*DE
- MeSH Heading
- Aspartic Acid|AA/TO; Cell Survival|DE; Cells, Cultured; Cysteic Acid|TO; Cysteine|AA/TO;
Fibroblasts|CY/DE; Human; In Vitro; Isomerism; Kainic Acid|TO; Kinetics; Support, U.S.
Gov't, P.H.S.; Time Factors
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0024-3205
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 0 (Glutamates); 1001-13-4 (homocysteic acid); 13100-82-8 (Cysteic Acid); 2381-08-0 (cysteine
sulfinic acid); 4371-52-2 (Cysteine); 454-28-4 (Homocysteine); 487-79-6
(Kainic Acid); 56-84-8 (Aspartic Acid); 56-86-0 (Glutamic Acid); 6384-92-5
(N-Methylaspartate)
Record 87 from database: MEDLINE
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- Title
- Management of early inflammatory arthritis. Genetic factors predicting persistent
disease: the role of defective enzyme systems.
- Author
- Waring RH; Emery P
- Address
-
- Source
- Baillieres Clin Rheumatol, 1992 Jun, 6:2, 337-50
- Abstract
- In this chapter, we investigate the use of non-toxic 'probe drugs' to give information
about basic biochemical pathways. We have examined the hypothesis that a major factor in
RA is defective metabolism of sulphur-containing compounds. At least two pathways have
been shown to be abnormal in RA. Generally, patients have reduced capacity to metabolize
and detoxify thiol compounds by methylation, and have increased levels of plasma cysteine.
They also have a lower capacity for S-oxidation of cysteine and its
derivatives, with reduced amounts of plasma sulphate. The raised cysteine
resulting from less effective metabolism may lead to reduced clearance of immune complexes
and a raised inflammatory response in RA patients. Lower plasma sulphate, however, leads
to defective tissue synthesis, and makes adequate repair of damaged joints less feasible.
The co-existence of defects in these two interacting endogenous pathways serves to
perpetuate the disease process, leading to chronic inflammation and tissue destruction.
These enzyme defects have been shown to be predictive of persistent disease.
- Language of Publication
- English
- Unique Identifier
- 92405185
- MeSH Heading (Major)
- Arthritis, Rheumatoid|EN/*GE/ME
- MeSH Heading
- Acetaminophen|ME; Carbocysteine|ME; Cysteine|ME; Forecasting; Human;
Metabolic Detoxication, Drug; Methylation; Methyltransferases|ME; Oxidation-Reduction;
Sulfates|ME
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0950-3579
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- EC 2.1.1. (Methyltransferases); EC 2.1.1.9 (thiol S-methyltransferase); 0 (Sulfates);
103-90-2 (Acetaminophen); 2387-59-9 (Carbocysteine); 4371-52-2 (Cysteine)
Record 88 from database: MEDLINE
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- Title
- Etorphine inhibits cell growth and induces apoptosis in SK-N-SH cells: involvement of
pertussis toxin-sensitive G proteins.
- Author
- Yin DL; Ren XH; Zheng ZL; Pu L; Jiang LZ; Ma L; Pei G
- Address
- Shanghai Institute of Cell Biology, Chinese Academy of Sciences, People's Republic of
China.
- Source
- Neurosci Res, 1997 Oct, 29:2, 121-7
- Abstract
- Opiates have been used extensively in the treatment of pain but with the severe side
effect of addiction, which is believed to be related to opiates' direct (primary) or
indirect (secondary) neurotoxicity. In this study, the effects of opioids on cell growth
and apoptosis have been examined in human neuroblastoma cell line SK-N-SH. Etorphine, a
wide-spectrum and potent agonist of opioid receptors, was found to significantly inhibit
cell growth and to induce apoptosis. The inhibitory and apoptotic activities of etorphine
followed a dose- and time-dependent manner. The more specific agonists of opioid receptors
such as morphine, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAGO), [D-Pen2,
D-Pen5]-enkephalin (DPDPE), dynorphin A and nociceptin/orphanin FQ did not show similar
toxic activities under the same conditions. In addition, the effects of etorphine could
not be blocked by the opioid receptor antagonist naloxone, suggesting that the effects of
etorphine might not be mediated by a classical opioid receptor. However, pretreatment of
SK-N-SH cells with pertussis toxin (PTX) blocked the inhibition of cell growth and
apoptosis induced by etorphine, indicating the involvement of PTX-sensitive G proteins in
the processes. It was also shown that etorphine-induced apoptosis was prevented by
actinomycin D (AD) and interleukin-1beta converting enzyme inhibitor I. Interestingly,
etorphine was similarly potent to inhibit growth of pheochromocytoma (PC12) cells but less
effective in SH-SY5Y neuroblastoma cells and C6 glioma cells. We propose that inhibition
of cell growth and induction of apoptosis may be one mechanism of opioid neurotoxicity.
- Language of Publication
- English
- Unique Identifier
- 98022418
- MeSH Heading (Major)
- Apoptosis|*/DE/PH; Etorphine|*PD; G-Proteins|*DE/*PH; Narcotics|*PD; Pertussis
Toxins|*PD
- MeSH Heading
- Animal; Cell Division|DE; Cysteine Proteinases|ME; Dactinomycin|PD;
Enzyme Inhibitors|PD; Human; Neurons|DE; PC12 Cells; Rats; Receptors, Opioid|PH; Support,
Non-U.S. Gov't; Tumor Cells, Cultured|DE
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0168-0102
- Country of Publication
- IRELAND
Record 89 from database: MEDLINE
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- Title
- Thiazolidine-4-carboxylic acid, a physiologic sulfhydryl antioxidant with potential
value in geriatric medicine.
- Author
- Weber HU; Fleming JF; Miquel J
- Address
-
- Source
- Arch Gerontol Geriatr, 1982 Dec, 1:4, 299-310
- Abstract
- Thiazolidine-4-carboxylic acid (TC) is a cyclic sulfur amino acid, a condensation
product of cysteine and formaldehyde. The chemistry, biological effects
and clinical use of TC are reviewed. Extensive animal experiments and studies on human
subjects carried out in Europe indicate that a combination of TC and folic acid,
'Folcysteine', has revitalizing effects on age-related biochemical variables of blood and
tissues. Further animal studies confirmed the anti-toxic effects of TC, particularly on
the liver. The evidence accumulated so far suggests that addition of TC to the diet slows
the aging process in mammals and prolongs their life span. On the other hand, findings
suggesting that TC caused reverse transformation of tumor cells into normal cells and was
effective against human cancers could not be confirmed in additional studies. TC has been
clinically used for about 20 yr, mainly in the treatment of liver diseases and related
gastrointestinal disturbances. Derivatives of TC with similar applications have been
developed. Djenkolic acid is a naturally occurring relative of TC which is abundant in
djenkol beans. The toxic effects of djenkolic acid and its possible conversion into TC are
discussed.
- Language of Publication
- English
- Unique Identifier
- 83307675
- MeSH Heading (Major)
- Antioxidants|ME/*TU; Thiazoles|ME/*TU
- MeSH Heading
- Aged; Animal; Chemistry; Cysteine|TU; Dogs; Drug Combinations|TU; Folic
Acid|TU; Gastrointestinal Diseases|DT; Human; Liver Diseases|DT; Longevity|DE; Mice; Rats
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0167-4943
- Country of Publication
- NETHERLANDS
- CAS Registry/EC Number
- 0 (Antioxidants); 0 (Drug Combinations); 0 (Thiazoles); 4371-52-2 (Cysteine);
444-27-9 (thiazolidine-4-carboxylic acid); 59-30-3 (Folic Acid); 8064-47-9 (folcysteine)
Record 90 from database: MEDLINE
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- Title
- Increased DT-diaphorase expression and cross-resistance to mitomycin C in a series of
cisplatin-resistant human ovarian cancer cell lines.
- Author
- ODwyer PJ; Perez RP; Yao KS; Godwin AK; Hamilton TC
- Address
- Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
- Source
- Biochem Pharmacol, 1996 Jul, 52:1, 21-7
- Abstract
- In a series of ovarian carcinoma cell lines selected in vitro for resistance to
cisplatin by continuous exposure to increasing drug concentrations, the level of
resistance is proportional to the expression of gamma-glutamylcysteine synthetase
(gamma-GCS). To determine if other detoxicating genes are coordinately expressed, we
measured the activity of DT-diaphorase and cytochrome P450 reductase. The specific
activity of DT-diaphorase, but not that of cytochrome P450 reductase, increased with
increasing resistance to cisplatin. Steady-state mRNA levels for DT-diaphorase correlated
with enzyme activity and hence with cisplatin resistance. Since the activity of
DT-diaphorase has been associated with sensitivity to quinones, we studied the
cytotoxicity of mitomycin C under oxic conditions. Unexpectedly, resistance to mitomycin C
increased proportionally with that to cisplatin (r = 0.997). Pretreatment with buthionine
sulfoximine, which inhibits glutathione (GSH) synthesis, failed to sensitize either the
sensitive or the resistant lines to mitomycin C. Thus, the basis for collateral resistance
to mitomycin C in the cisplatin-resistant lines under oxic conditions is unrelated to
overproduction of GSH. Under hypoxia, the toxicity of mitomycin C to the most sensitive
(A2780) cell line was unchanged. However, the most resistant (C200) line was 2-fold more
resistant to mitomycin C under hypoxic conditions. The coordinate overexpression of
DT-diaphorase and gamma-GCS in the resistant cell lines is thus associated with hypoxic
cell resistance, and supports the involvement of shared mechanisms of gene regulation in
the observed resistant phenotype.
- Language of Publication
- English
- Unique Identifier
- 96276438
- MeSH Heading (Major)
- Antineoplastic Agents|*PD; Cisplatin|*PD; Mitomycin C|*PD; NAD(P)H Dehydrogenase
(Quinone)|*GE/ME; Ovarian Neoplasms|EN/*PA
- MeSH Heading
- Cell Hypoxia; Drug Resistance, Neoplasm; Female; Glutamate-Cysteine
Ligase|ME; Glutathione|ME; Human; RNA, Messenger|GE/ME; Support, U.S. Gov't, P.H.S.; Tumor
Cells, Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0006-2952
- Country of Publication
- ENGLAND
Record 91 from database: MEDLINE
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- Title
- Central nervous system cytokines and their relevance for neurotoxicity and apoptosis.
- Author
- Licinio J
- Address
- Clinical Neuroendocrinology Branch, National Institute of Mental Health, National
Institutes of Health, Bethesda, MD, USA.
- Source
- J Neural Transm Suppl, 1997, 49:, 169-75
- Abstract
- Cytokines are molecules that are synthesized not only by the immune system, but also by
cells in the central nervous system, including neurons, glia, and brain vascular cells. In
the brain, cytokines can be neuroprotective or they can contribute to neurodegeneration.
The role of cytokines in the regulation of normal and abnormal brain function represents a
rapidly growing frontier in neuroscience. Cytokines are pleiotropic and redundant, and
they can modulate the effects of neurotransmitters and neuropeptides; thus, in order to
understand the effects of brain cytokines on apoptosis and toxicity, it is necessary to
study the temporal and spatial expression of complex networks of cytokines, growth
factors, neuropeptides, and neurotransmitters. This effort is currently in progress in
many centers. Modulation of cytokine function in the central nervous system represents a
new therapeutic strategy for neurodegeneration.
- Language of Publication
- English
- Unique Identifier
- 97411448
- MeSH Heading (Major)
- Apoptosis|*; Brain|CY/IM/*PH; Cytokines|*PH; Neurons|CY/IM/*PH; Neurotoxins|*
- MeSH Heading
- Animal; Cerebrovascular Circulation; Cysteine Proteinases|ME; Human;
Necrosis; Nerve Degeneration; Neuroglia|CY/IM/PH; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0303-6995
- Country of Publication
- AUSTRIA
Record 92 from database: MEDLINE
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- Title
- Degradation of oxidized proteins in mammalian cells.
- Author
- Grune T; Reinheckel T; Davies KJ
- Address
- The Andrus Gerontology Center, University of Southern California, Los Angeles
90089-0191, USA.
- Source
- FASEB J, 1997 Jun, 11:7, 526-34
- Abstract
- Protein oxidation in vivo is a natural consequence of aerobic life. Oxygen radicals and
other activated oxygen species generated as by-products of cellular metabolism or from
environmental sources cause modifications to the amino acids of proteins that generally
result in loss of protein function/enzymatic activity. Oxidatively modified proteins can
undergo direct chemical fragmentation or can form large aggregates due to covalent
cross-linking reactions and increased surface hydrophobicity. Mammalian cells exhibit only
limited direct repair mechanisms and most oxidized proteins undergo selective proteolysis.
The proteasome appears to be largely responsible for the degradation of soluble
intracellular proteins. In most cells, oxidized proteins are cleaved in an ATP-and
ubiquitin-independent pathway by the 20 S "core" proteasome. The proteasome
complex recognizes hydrophobic amino acid residues, aromatic residues, and bulky aliphatic
residues that are exposed during the oxidative rearrangement of secondary and tertiary
protein structure: increased surface hydrophobicity is a feature common to all oxidized
proteins so far tested. The recognition of such (normally shielded) hydrophobic residues
is the suggested mechanism by which proteasome catalyzes the selective removal of
oxidatively modified cell proteins. By minimizing protein aggregation and cross-linking
and by removing potentially toxic protein fragments, proteasome plays a key role in the
overall antioxidant defenses that minimize the ravages of aging and disease.
- Language of Publication
- English
- Unique Identifier
- 97355595
- MeSH Heading (Major)
- Proteins|*ME
- MeSH Heading
- Amino Acids|ME; Animal; Antioxidants|ME; Cysteine Proteinases|ME;
Human; Mammals; Membrane Proteins|ME; Multienzyme Complexes|ME; Organelles|ME;
Oxidation-Reduction; Solubility; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0892-6638
- Country of Publication
- UNITED STATES
Record 93 from database: MEDLINE
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- Title
- Chelation of mercury by polymercaptal microspheres: new potential antidote for mercury
poisoning.
- Author
- Margel S; Hirsh J
- Address
-
- Source
- J Pharm Sci, 1982 Sep, 71:9, 1030-4
- Abstract
- Newly synthesized polymercaptal microspheres of 0.8 +/- 0.02 micron were shown to have a
specific and fast intake of mercury compounds over a whole range of pH while maintaining
low toxicity. The microspheres bind easily with mercury compounds which are already bound
to the biological mercury binders, albumin or cysteine. Mercury was
recovered completely from the microspheres by using a solution of thiourea in hydrochloric
acid. Due to their high surface area, low toxicity, and strong affinity toward mercury
compounds, the microspheres have a potential use as a new oral drug for treatment in cases
of mercury poisoning.
- Language of Publication
- English
- Unique Identifier
- 83033042
- MeSH Heading (Major)
- Antidotes|*; Chelating Agents|*PD; Mercury Poisoning|*DT; Polymers|*PD; Sulfhydryl
Compounds|*PD
- MeSH Heading
- Cysteine; Human; Hydrogen-Ion Concentration; Lethal Dose 50;
Microspheres; Protein Binding; Serum Albumin|ME; Support, Non-U.S. Gov't; Time Factors
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0022-3549
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Antidotes); 0 (Chelating Agents); 0 (Polymers); 0 (Serum Albumin); 0 (Sulfhydryl
Compounds); 4371-52-2 (Cysteine); 66397-14-6 (polymercaptal)
Record 94 from database: MEDLINE
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- Title
- Bcl-2 prevents nitric oxide-mediated apoptosis and poly(ADP-ribose) polymerase cleavage.
- Author
- Melková Z; Lee SB; Rodriguez D; Esteban M
- Address
- Department of Biochemistry, SUNY, Brooklyn 11203, USA.
- Source
- FEBS Lett, 1997 Feb, 403:3, 273-8
- Abstract
- Toxic effects of nitric oxide (NO) were suggested to be mediated by its metabolite
peroxynitrite, a strong oxidizing agent. To determine if antioxidative effects of Bcl-2
protooncogene can prevent NO-mediated apoptosis, we used vaccinia virus recombinants
expressing mouse inducible NO-synthase, iNOS, or human bcl-2 genes. Expression of iNOS in
HeLa G cells induces apoptosis which can be prevented by co-expression of bcl-2 or by
addition of reduced glutathione or N-acetylcysteine. We demonstrate that this NO-induced
apoptosis proceeds through the activation of interleukin-1 beta-converting enzyme-like
proteases and cleavage of the poly(ADP-ribose) polymerase, an effect which is also
prevented by Bcl-2.
- Language of Publication
- English
- Unique Identifier
- 97226654
- MeSH Heading (Major)
- Apoptosis|*PH; Nitric Oxide|*PH; NAD+ ADP-Ribosyltransferase|*BI/ME; Proto-Oncogene
Proteins c-bcl-2|*PH
- MeSH Heading
- Acetylcysteine|PD; Animal; Chlorides|PD; Cysteine Proteinases|ME;
DNA|BI; Gene Expression; Genes, bcl-2|GE; Genetic Vectors; Glutathione|PD; Hela Cells;
Human; Isopropyl Thiogalactoside; Lipid Peroxidation; Mice; Nitric-Oxide Synthase|GE;
Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.; Thiobarbituric Acid Reactive
Substances|AN; Vaccinia Virus|GD; Zinc Compounds|PD
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0014-5793
- Country of Publication
- NETHERLANDS
Record 95 from database: MEDLINE
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- Title
- Chemical debridement of burns: mercaptans.
- Author
- Levenson SM; Gruber DK; Gruber C; Lent R; Seifter E
- Address
-
- Source
- J Trauma, 1981 Aug, 21:8, 632-44
- Abstract
- Experiments were conducted using non-enzymatic chemical agents (with emphasis on certain
mercaptans), alone, in conjunction with enzymatic agents and/or other nonenzymatic
chemicals for debridement of burns. Both in vitro (rats, pigs, humans) and in vivo (rats,
pigs) tests were carried out. N-acetylcysteine, penicillamine and cysteine
ethyl ester in low to moderate concentrations accelerate the debriding action of bromelain
(an enzymatic preparation from pineapple stems) and in higher concentrations,
N-acetylcysteine and penicillamine (cysteine ethyl ester was not tested)
cause ready separation of the burn eschar from the underlying tissue before solubilization
of the eschar is complete (rat) or has occurred (pig). Debridement of 3 degree burns of
rats is complete within 4-6 hours; the take of immediately applied syngeneic skin grafts
is complete and permanent. This is first time rapid debridement of 3 degree burns
permitting immediate successful skin grafting has been accomplished with known defined
chemicals. In pigs there is softening of the 3 degree burn eschar by N-acetylcysteine but
little, if any, dissolution of the eschar. However, mechanical separation of the eschar
from the underlying tissue is accomplished readily with a wooden throat stick with no
bleeding. There is a change in color of the superficial layer of the underlying
subcutaneous tissue from yellow-light brown to dark brown-black. The debrided areas begin
to granulate promptly. The healing of deep dermal burns of pigs is hastened by the
application of N-acetylcysteine for a day (beginning 24 hours after burning) while the
healing of moderately deep dermal burns is not modified. Unburned skin is not damaged.
There is no apparent systemic toxicity associated with the use of N-acetylcysteine for
debridement of 10-15% b.s.a. 3 degree burns of rats or 15-20% b.s.a. 3 degree burns of
pigs. Major emphasis has been on N-acetylcysteine because of the potential adverse
secondary effect of penicillamine and cysteine ethyl ester;
N-acetylcysteine is readily metabolized. The use of a keratolytic agent prior to the
application of N-acetylcysteine hastens the latter's action. Sulfamylon and sulfadiazine
can be used with N-acetylcysteine without interfering with its debriding action. The
effects of the mercaptans are likely due largely to their ability to depolymerize
connective tissue proteoglycans and proteins, especially at the interface between living
and dead tissue.
- Language of Publication
- English
- Unique Identifier
- 81267549
- MeSH Heading (Major)
- Burns|*SU; Debridement|*MT; Sulfhydryl Compounds|*TU
- MeSH Heading
- Acetylcysteine|TU; Animal; Bromelains|TU; Cysteine|AA/TU; Drug
Screening; Human; Male; Mercaptoethanol|TU; Penicillamine|TU; Rats; Rats, Inbred Strains;
Support, U.S. Gov't, P.H.S.; Swine
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0022-5282
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 3.4.22.4 (Bromelains); 0 (Sulfhydryl Compounds); 3411-58-3 (ethyl cysteine);
4371-52-2 (Cysteine); 52-67-5 (Penicillamine); 60-24-2 (Mercaptoethanol);
616-91-1 (Acetylcysteine)
Record 96 from database: MEDLINE
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- Title
- Role of superoxide and hydrogen peroxide in cell lysis during irradiation in vitro of
Ehrlich ascitic carcinoma cells in the presence of melanin.
- Author
- Menon IA; Persad S; Ranadive NS; Haberman HF
- Address
-
- Source
- Can J Biochem Cell Biol, 1985 Apr, 63:4, 278-83
- Abstract
- The reactive species involved in the cell lysis during ultraviolet irradiation of
Ehrlich ascitic carcinoma cells in the presence of red hair melanin (RHM) were
investigated by determining 51Cr release from labeled cells. Cysteine at
1 mM in the presence of RHM increased the cell lysis during the incubation in the dark as
well as during irradiation; this lysis was enhanced by superoxide dismutase (SOD).
Catalase abolished the dark reaction and inhibited the cysteine-induced
increase of cell lysis during irradiation. The cell lysis by the superoxide-generating
xanthine oxidase system was not significantly increased by SOD, but was significantly
decreased by nitroblue tetrazolium and completely abolished by catalase. The cell lysis
induced by the supernatants obtained from the suspensions of RHM either irradiated alone
or with cysteine was abolished by catalase. Sediments of irradiated RHM
when incubated in the dark with the cells did not release 51Cr. Irradiation of the cells
in the presence of the same sediments produced lysis which was not inhibited by catalase.
These studies suggest that superoxide per se is not toxic to the cells, but the H2O2
formed by dismutation of superoxide produces cell lysis either directly or by generating
OH through Fenton-type reactions. A large part of the cell lysis seen during irradiation
of cells in the presence of RHM is not due to H2O2, but may possibly be due to the melanin
free radicals formed during irradiation.
- Language of Publication
- English
- Unique Identifier
- 85254077
- MeSH Heading (Major)
- Carcinoma, Ehrlich Tumor|ME/*PA; Cell Survival|DE/*RE; Hydrogen Peroxide|*ME;
Melanins|*PD; Superoxides|*ME; Ultraviolet Rays|*
- MeSH Heading
- Animal; Catalase|PD; Chromium Radioisotopes|DU; Cysteine|PD; Hair;
Human; Mice; Superoxide Dismutase|PD; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0714-7511
- Country of Publication
- CANADA
- CAS Registry/EC Number
- EC 1.11.1.6 (Catalase); EC 1.15.1.1 (Superoxide Dismutase); 0 (Chromium Radioisotopes);
0 (Melanins); 11062-77-4 (Superoxides); 4371-52-2 (Cysteine); 7722-84-1
(Hydrogen Peroxide)
Record 97 from database: MEDLINE
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- Title
- The disposition of paracetamol and its conjugates during multiple dosing in patients
with end-stage renal failure maintained on haemodialysis.
- Author
- Martin U; Temple RM; Winney RJ; Prescott LF
- Address
- University Department of Clinical Pharmacology, Royal Infirmary, Edinburgh, UK.
- Source
- Eur J Clin Pharmacol, 1993, 45:2, 141-5
- Abstract
- The disposition of oral paracetamol (1.0 g 3 times daily for 10 days) was studied in 6
patients with end-stage renal failure (creatinine clearance < 5 ml x min-1) maintained
on haemodialysis 2 or 3 times per week. Blood was sampled daily for 10 days. The time of
sampling depended on whether the patients were dialysed in the morning or afternoon but
was always within 5 h of the last dose of paracetamol. On dialysis days samples were taken
at the start of the session. The mean plasma concentration of paracetamol was 6.8 mg x l-1
after the first 24 h and subsequently varied little throughout the 10 days. Apparent
steady-state plasma concentrations of 60.0 mg x l-1 and 54.5 mg x l-1 were reached for the
glucuronide and sulphate conjugate of paracetamol respectively by the 2nd day of treatment
with little variation throughout the remainder of the study. These steady-state
concentrations of paracetamol glucuronide and sulphate were much lower than predicted. The
steady-state plasma concentrations of the retained cysteine and
mercapturate conjugates of paracetamol were low (5.7 and 3.7 mg x l-1, respectively) and
there was no evidence of accumulation of these potentially toxic metabolites. It is not
clear why regular dosing with paracetamol in haemodialysis patients did not cause the
accumulation of paracetamol glucuronide or sulphate as predicted. There may be
enterohepatic elimination of retained paracetamol conjugates or depletion of substrates
such as inorganic sulphate during chronic dosing.
- Language of Publication
- English
- Unique Identifier
- 94039353
- MeSH Heading (Major)
- Acetaminophen|*AA/AD/BL/*PK; Acetylcysteine|*AA/PK; Cysteine|*AA/PK;
Hemodialysis|*; Kidney Failure, Chronic|*ME/TH
- MeSH Heading
- Administration, Oral; Adult; Drug Administration Schedule; Female; Human; Male; Middle
Age
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0031-6970
- Country of Publication
- GERMANY
- CAS Registry/EC Number
- 10066-90-7 (acetaminophen sulfate ester); 103-90-2 (Acetaminophen); 16110-10-4
(acetaminophen glucuronide); 4371-52-2 (Cysteine); 55748-93-1
(paracetamol mercapturate); 58109-87-8 (paracetamol cysteine); 616-91-1
(Acetylcysteine)
Record 98 from database: MEDLINE
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- Title
- Thiol status and cytopathological effects of acrolein in normal and xeroderma
pigmentosum skin fibroblasts.
- Author
- Dypbukt JM; Atzori L; Edman CC; Grafström RC
- Address
- Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
- Source
- Carcinogenesis, 1993 May, 14:5, 975-80
- Abstract
- Thiol redox status was determined in normal human skin fibroblasts and a DNA
repair-deficient xeroderma pigmentosum (XP) fibroblast cell line (XP12BE, group A), and
cytotoxic and genotoxic effects of the thiol-reactive aldehyde acrolein were studied in
these cell types. Normal cells contained higher amounts of the reduced glutathione and cysteine
respectively, and higher amounts of these thiols as protein-bound disulfides than the XP
cells. However, in both cell types total glutathione was present in 6- to 7-fold higher
amounts than total cysteine, and total protein thiols corresponded to
approximately 30% of total thiols. A 1 h exposure to acrolein caused a quantitatively
similar depletion of reduced glutathione and free protein thiols in both cell types,
without causing changes in the thiol redox state. However, acrolein caused higher toxicity
measured as trypan blue exclusion, and also a higher extent of DNA single-strand breaks in
the XP cells than in the normal cells. Exposure to acrolein, followed by incubation in
fresh medium resulted in continued formation of DNA single-strand breaks in the normal
cells, whereas no such accumulation occurred in the XP cells. In the normal cells, the DNA
single-strand breaks accumulated to a similar extent as in the presence of
1-beta-D-arabinofuranosyl-cytosine and hydroxyurea, i.e. two agents which together
efficiently inhibit DNA repair synthesis. The results indicate quantitative and
qualitative differences in the thiol redox state between normal and XP cells, and that
these differences may contribute to the higher cytotoxicity and genotoxicity of acrolein
in XP cells. Moreover, the results indicate that acrolein is a potent inhibitor of DNA
excision repair.
- Language of Publication
- English
- Unique Identifier
- 93278797
- MeSH Heading (Major)
- Acrolein|*PD/TO; DNA Damage|*; Skin|DE/*ME/PA; Sulfhydryl Compounds|*ME
- MeSH Heading
- Cell Line; Comparative Study; Cysteine|ME; Dose-Response Relationship,
Drug; Fibroblasts|DE/ME/PA; Glutathione|ME; Human; Oxidation-Reduction; Proteins|ME;
Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Xeroderma Pigmentosum
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0143-3334
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Proteins); 0 (Sulfhydryl Compounds); 107-02-8 (Acrolein); 4371-52-2 (Cysteine);
70-18-8 (Glutathione)
Record 99 from database: MEDLINE
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- Title
- Homocysteine levels in patients with rheumatoid arthritis treated with low-dose
methotrexate.
- Author
- Morgan SL; Baggott JE; Refsum H; Ueland PM
- Address
- Department of Nutrition Sciences, University of Alabama, Birmingham 35294.
- Source
- Clin Pharmacol Ther, 1991 Nov, 50:5 Pt 1, 547-56
- Abstract
- Plasma homocysteine levels were determined in patients who participated in a randomized,
double-blind placebo-controlled trial of folate supplementation (1 mg/day) during
methotrexate therapy for rheumatoid arthritis. Plasma and red blood cell folate levels
before methotrexate therapy were significantly negatively correlated with homocysteine
levels. Homocysteine levels were not significantly correlated with the initial C1 index
(an assay that measures the folate status of blood mononuclear cells) or the C1 index
during methotrexate therapy. There was no significant difference in homocysteine levels
between pretreatment and levels drawn at 3 or 6 months. Initial homocysteine levels were
predictive of toxicities, such as gastrointestinal intolerance and elevations of liver
enzymes in the placebo group. There was no significant correlation between occurrence of
toxicity and initial homocysteine levels in the folic acid-supplemented group.
Homocysteine levels were not predictive of the efficacy of methotrexate therapy. We
conclude that plasma homocysteine levels are correlated with plasma and red blood cell
folate levels before methotrexate therapy but is not correlated with folate status in
blood mononuclear cells.
- Language of Publication
- English
- Unique Identifier
- 92036044
- MeSH Heading (Major)
- Arthritis, Rheumatoid|BL/*DT; Folic Acid|BL/*TU; Homocysteine|*BL; Methotrexate|*TU
- MeSH Heading
- Cysteine|BL; Double-Blind Method; Female; Human; Male; Support,
Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL
- ISSN
- 0009-9236
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 4371-52-2 (Cysteine); 454-28-4 (Homocysteine); 59-05-2 (Methotrexate);
59-30-3 (Folic Acid)
Record 100 from database: MEDLINE
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- Title
- Development of low- and high-serum culture conditions for use of human oral fibroblasts
in toxicity testing of dental materials.
- Author
- Liu Y; Arvidson K; Atzori L; Sundqvist K; Silva B; Cotgreave I; Grafström RC
- Address
- Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
- Source
- J Dent Res, 1991 Jul, 70:7, 1068-73
- Abstract
- With the aim of establishing conditions applicable to the testing of dental materials in
human target cells, fibroblastic cell lines have been derived and grown from explants of
human oral mucosa. Both a high-serum medium (termed "HSM") (CMRL 1066
supplemented with 10% fetal bovine serum) and a low-serum medium (termed "LSM")
(a 1:1 mixture of M 199:MCDB 153 supplemented with 1.25% serum) supported radial
outgrowths of cells from oral explants, as well as the subsequent transfer and growth of
the cells in mass culture and at clonal density. Cells were typically fibroblastic in that
they expressed vimentin uniformly, but did not express immunocytochemical markers of
epithelial or endothelial cells. Cells derived in either LSM or HSM showed significantly
higher colony-forming efficiency and clonal growth rate when transferred in LSM, as
compared with HSM. Because cell migration occurred to a lesser extent in LSM, microscopic
scoring of colony formation was also markedly facilitated. In both LSM and HSM, cellular
low-molecular-weight thiols constituted about 30% of the total amount of sulfhydryls.
Glutathione was present in about six- to seven-fold-higher amounts than cysteine--glutathione
primarily in its reduced form and cysteine primarily in its oxidized
form. A corrosion product of dental amalgam, i.e., Hg2+, decreased cell survival measured
as colony-forming efficiency in a dose-dependent manner following either an acute (one h)
exposure or continuous exposure (seven days). These studies demonstrated that human oral
fibroblasts could be cultured at about one-tenth of the serum content that is commonly
used.(ABSTRACT TRUNCATED AT 250 WORDS)
- Language of Publication
- English
- Unique Identifier
- 91294432
- MeSH Heading (Major)
- Culture Media|*; Dental Materials|*TO; Fibroblasts|*DE; Materials Testing|*MT;
Toxicology|*MT
- MeSH Heading
- Blood; Cell Count; Cell Movement; Cysteine|AN; Glutathione|AN; Human;
Immunohistochemistry; Mercury|TO; Mouth Mucosa|CY; Sulfhydryl Compounds|AN; Support,
Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0022-0345
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Culture Media); 0 (Dental Materials); 0 (Sulfhydryl Compounds); 4371-52-2 (Cysteine);
70-18-8 (Glutathione); 7439-97-6 (Mercury)
Record 101 from database: MEDLINE
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- Title
- Cadmium resistance in A549 cells correlates with elevated glutathione content but not
antioxidant enzymatic activities.
- Author
- Hatcher EL; Chen Y; Kang YJ
- Address
- Department of Pharmacology and Toxicology, University of North Dakota School of
Medicine, Grand Forks, USA.
- Source
- Free Radic Biol Med, 1995 Dec, 19:6, 805-12
- Abstract
- Glutathione has been implicated to function in cytoprotection against cadmium toxicity.
The mechanism by which glutathione plays this role has not been well understood. Because
glutathione is an important antioxidant and several studies have shown that cadmium
induces oxidative stress, this study was undertaken to determine whether development of
cadmium resistance is linked to enhanced antioxidant activities. A cadmium-resistant
subpopulation of human lung carcinoma A549 cells, which was developed by repeatedly
exposing the cells to step-wise increased cadmium concentrations, was compared to a
cadmium-sensitive one. The acquired cadmium resistance resulted from neither decreased
cadmium uptake nor enhanced cellular metallothionein synthesis. Glutathione content,
however, was markedly elevated in the cadmium-resistant cells. In contrast, the activities
of the glutathione redox cycle related enzymes, glutathione peroxidase and reductase, were
unchanged. Two other antioxidant enzymes, superoxide dismutase and catalase, were also not
altered. The results suggest that the development of cadmium resistance in A549 cells
unlikely results from enhanced antioxidant enzyme activities, although it is associated
with elevated cellular glutathione levels. In addition, measurement of the mRNA and DNA
levels for gamma-glutamylcysteine synthetase, the rate-limiting enzyme for glutathione
biosynthesis, revealed that enhanced expression of the enzyme but not gene amplification
is likely responsible for the elevation of cellular glutathione levels.
- Language of Publication
- English
- Unique Identifier
- 96128476
- MeSH Heading (Major)
- Antioxidants|*ME; Cadmium|*PD; Drug Resistance|*; Glutathione|*ME; Lung Neoplasms|*ME;
Oxidative Stress|*
- MeSH Heading
- DNA|AN; Glutamate-Cysteine Ligase|GE; Human; Oxidation-Reduction; RNA,
Messenger|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Tumor Cells,
Cultured
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0891-5849
- Country of Publication
- UNITED STATES
Record 102 from database: MEDLINE
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- Title
- Thiol status and cytopathological effects of acrolein in normal and xeroderma
pigmentosum skin fibroblasts.
- Author
- Dypbukt JM; Atzori L; Edman CC; Grafström RC
- Address
- Department of Toxicology, Karolinska Institutet, Stockholm, Sweden.
- Source
- Carcinogenesis, 1993 May, 14:5, 975-80
- Abstract
- Thiol redox status was determined in normal human skin fibroblasts and a DNA
repair-deficient xeroderma pigmentosum (XP) fibroblast cell line (XP12BE, group A), and
cytotoxic and genotoxic effects of the thiol-reactive aldehyde acrolein were studied in
these cell types. Normal cells contained higher amounts of the reduced glutathione and cysteine
respectively, and higher amounts of these thiols as protein-bound disulfides than the XP
cells. However, in both cell types total glutathione was present in 6- to 7-fold higher
amounts than total cysteine, and total protein thiols corresponded to
approximately 30% of total thiols. A 1 h exposure to acrolein caused a quantitatively
similar depletion of reduced glutathione and free protein thiols in both cell types,
without causing changes in the thiol redox state. However, acrolein caused higher toxicity
measured as trypan blue exclusion, and also a higher extent of DNA single-strand breaks in
the XP cells than in the normal cells. Exposure to acrolein, followed by incubation in
fresh medium resulted in continued formation of DNA single-strand breaks in the normal
cells, whereas no such accumulation occurred in the XP cells. In the normal cells, the DNA
single-strand breaks accumulated to a similar extent as in the presence of
1-beta-D-arabinofuranosyl-cytosine and hydroxyurea, i.e. two agents which together
efficiently inhibit DNA repair synthesis. The results indicate quantitative and
qualitative differences in the thiol redox state between normal and XP cells, and that
these differences may contribute to the higher cytotoxicity and genotoxicity of acrolein
in XP cells. Moreover, the results indicate that acrolein is a potent inhibitor of DNA
excision repair.
- Language of Publication
- English
- Unique Identifier
- 93278797
- MeSH Heading (Major)
- Acrolein|*PD/TO; DNA Damage|*; Skin|DE/*ME/PA; Sulfhydryl Compounds|*ME
- MeSH Heading
- Cell Line; Comparative Study; Cysteine|ME; Dose-Response Relationship,
Drug; Fibroblasts|DE/ME/PA; Glutathione|ME; Human; Oxidation-Reduction; Proteins|ME;
Support, Non-U.S. Gov't; Support, U.S. Gov't, Non-P.H.S.; Xeroderma Pigmentosum
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0143-3334
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Proteins); 0 (Sulfhydryl Compounds); 107-02-8 (Acrolein); 4371-52-2 (Cysteine);
70-18-8 (Glutathione)
Record 103 from database: MEDLINE
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- Title
- The total free radical trapping ability of blood plasma in eclampsia.
- Author
- Jendryczko A; Tomala J
- Address
- Department of Drug Chemistry, Silesian Medical School, Katowice.
- Source
- Zentralbl Gynakol, 1995, 117:3, 126-9
- Abstract
- The interaction between various antioxidants may be important in protecting against
oxygen toxicity. We studied the total radical trapping capacity of the antioxidants in
plasma (TRAP) and compared the TRAP-level in the patients with eclampsia with that in
normal pregnant women. The measured and calculated TRAP-level was higher in the control
group than in the group with eclampsia. The uric acid, vitamins E and C and sulfide
concentrations were lower in the group of women with eclampsia compared with the controls.
The central conclusion from this work is that for patients with eclampsia, the plasma
concentrations of the essential nutrients: vitamin E, vitamin C, and cysteinerich protein
are too low for optimal antioxidant systems activities.
- Language of Publication
- English
- Unique Identifier
- 95259400
- MeSH Heading (Major)
- Antioxidants|*PK; Eclampsia|*BL; Reactive Oxygen Species|*ME
- MeSH Heading
- Adult; Ascorbic Acid|BL; Cysteine|BL; Female; Free Radicals; Human;
Infant, Newborn; Pregnancy; Vitamin E|BL
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0044-4197
- Country of Publication
- GERMANY
Record 104 from database: MEDLINE
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- Title
- Solubility of silver sulfadiazine in physiological media and relevance to treatment of
thermal burns with silver sulfadiazine cream.
- Author
- Tsipouras N; Rix CJ; Brady PH
- Address
- Department of Applied Chemistry, Royal Melbourne Institute of Technology, Victoria,
Australia.
- Source
- Clin Chem, 1995 Jan, 41:1, 87-91
- Abstract
- Silver sulfadiazine cream has been a standard treatment for burns over the past two
decades. Although many studies have described the phenomenon of silver absorption from
burn wounds treated with silver sulfadiazine, they failed to examine the chemistry
underlying the absorption process: Silver chloride was assumed to form at the burn wound
and absorption of silver was believed to be negligible. Here we have developed chemical
model systems to investigate the interactions of silver sulfadiazine and silver chloride
in direct contact with synthetic serum electrolyte solution (SSES), with SSES plus
endogenous ligands or beef blood plasma, and with human serum. The results indicate that
silver absorption from an acute burn site can be significant, because human serum is
capable of solubilizing silver. This finding is of concern, given the potential for silver
toxicity as a direct consequence of applying silver sulfadiazine to extensive burn wounds.
- Language of Publication
- English
- Unique Identifier
- 95112426
- MeSH Heading (Major)
- Burns|*DT; Silver Sulfadiazine|*CH/*TU
- MeSH Heading
- Absorption; Cysteine|PD; Glutathione|PD; Histamine|PD; Human;
Methionine|PD; Ointments; Precipitation; Silver|AE/BL/ME; Silver Compounds|CH; Solubility;
Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0009-9147
- Country of Publication
- UNITED STATES
Record 105 from database: MEDLINE
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- Title
- A C terminus cysteine of diphtheria toxin B chain involved in
immunotoxin cell penetration and cytotoxicity.
- Author
- Dell'Arciprete L; Colombatti M; Rappuoli R; Tridente G
- Address
- Istituto di Scienze Immunologiche, University of Verona, Italy.
- Source
- J Immunol, 1988 Apr 1, 140:7, 2466-71
- Abstract
- The role of diphtheria toxin (DT) B-chain subdomains in DT cytotoxicity and immunotoxin
mechanism of action has been investigated. OKT3 (mAb to the CD3 surface Ag of human T
lymphocytes) was conjugated to DT or the DT mutant CRM 1001, which has a cys----tyr
substitution at position 471 of the B chain. OKT3-CRM 1001 immunotoxin was about 1400-fold
less cytotoxic for CD3 Jurkat cells than OKT3-DT and had a 12-fold slower kinetics of
protein synthesis inactivation, CRM 1001 killed DT-sensitive Vero cells at a 5000-fold
higher concentration than DT. Its cell surface-binding activity was comparable to DT.
Based on kinetics of cell inactivation, toxicity determination at low extracellular pH and
Triton X-114 distribution, it was concluded that CRM 1001 is defective in at least one
crucial step of toxin penetration and is unable to cross cell membranes as efficiently as
DT. The substituted cysteine appears to be important for DT translocating
functions. Data on the function of DT B-chain subdomains are relevant for the study of
whole toxin conjugates and their mechanism of action.
- Language of Publication
- English
- Unique Identifier
- 88170835
- MeSH Heading (Major)
- Cysteine|*IM/ME; Cytotoxicity, Immunologic|*/DE; Diphtheria
Toxin|*IM/ME/TO; Immunotoxins|AN/ME/*TO
- MeSH Heading
- Animal; Antigens, Differentiation, T-Lymphocyte|IM; Binding Sites, Antibody; Binding,
Competitive; Cross Reactions; Human; Hydrogen-Ion Concentration; Kinetics; Peptide
Fragments|IM/ME/TO; Polyethylene Glycols; Support, Non-U.S. Gov't; Vero Cells|IM
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0022-1767
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (diphtheria toxin fragment B); 0 (Antigens, CD3); 0 (Antigens, Differentiation,
T-Lymphocyte); 0 (Binding Sites, Antibody); 0 (Diphtheria Toxin); 0 (Immunotoxins); 0
(Peptide Fragments); 0 (Polyethylene Glycols); 4371-52-2 (Cysteine);
9036-19-5 (Nonidet P-40)
Record 106 from database: MEDLINE
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- Title
- SA 96 (N-(2-mercapto-2-methylpropanoyl)-L-cysteine) in rheumatoid
arthritis.
- Author
- Ishikawa K; Sakaguchi M
- Address
-
- Source
- Scand J Rheumatol, 1986, 15:1, 85-90
- Abstract
- SA 96 (N-(2-mercapto-2-methylpropanoyl)-L-cysteine) is a new sulfhydryl
compound having a relatively similar chemical structure to Tiopronin and D-penicillamine.
An open trial of SA 96 treatment (300 mg/day after meals for 16 weeks) was carried out in
11 patients with definite or classical rheumatoid arthritis and with therapeutic failure
of previous gold salts and/or D-penicillamine therapy. Two cases were withdrawn from the
trial, because of a side effect (hepatitis) in one patient and an unrelated illness in
another. The results in the 9 patients completing the trial demonstrated statistically
significant improvement in the clinical and laboratory measurements. A marked abatement of
disease activity was noted in 5 of 9 patients who did not benefit from, or suffered a
relapse during previous chrysotherapy and in 1 of 5 patients without benefit, or with
relapse following previous D-penicillamine treatment. Among 4 patients who had
discontinued D-penicillamine because of its intolerable cutaneous side effects, 3 patients
completed the trial, with favourable results. The results of this trial seem to indicate
that SA 96 is possibly of value as a slow-acting antirheumatic drug in some patients with
therapeutic failure of gold salts or D-penicillamine.
- Language of Publication
- English
- Unique Identifier
- 86179711
- MeSH Heading (Major)
- Anti-Inflammatory Agents|AE/*TU; Arthritis, Rheumatoid|*DT; Cysteine|*AA/AE/TU
- MeSH Heading
- Adult; Aged; Clinical Trials; Comparative Study; Drug Eruptions|ET; Elasticity; Female;
Gold|TU; Hepatitis, Toxic|ET; Human; Middle Age; Penicillamine|TU; Tensile Strength; Time
Factors
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE
- ISSN
- 0300-9742
- Country of Publication
- SWEDEN
- CAS Registry/EC Number
- 4371-52-2 (Cysteine); 52-67-5 (Penicillamine); 65002-17-7
(bucillamine); 7440-57-5 (Gold)
Record 107 from database: MEDLINE
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- Title
- Elevated plasma glutamate concentrations in HIV-1-infected patients may contribute to
loss of macrophage and lymphocyte functions.
- Author
- Eck HP; Frey H; Dröge W
- Address
- Institute of Immunology and Genetics, German Cancer Research Center, Heidelberg.
- Source
- Int Immunol, 1989, 1:4, 367-72
- Abstract
- We tested the hypothesis that the loss of immunological reactivity in HIV-1-infected
persons may result partly from a virus-induced metabolic disorder. Patients who are
infected with the acquired immunodeficiency syndrome (AIDS)-associated human
immunodeficiency virus 1 were found to have, on average, markedly elevated and highly
variable plasma glutamate concentrations. A similar elevation of the extracellular
glutamate concentration was found to inhibit DNA synthesis in cultures of mitogenically
stimulated lymphocytes. An even stronger inhibition was seen with the structural analogue
quisqualate, and a moderate inhibition was seen with N-methyl-D-aspartate and kainate,
i.e. with well established pharmacological probes for the excitatory glutamate receptors
in the vertebrate central nervous system. The inhibitory effect of glutamate was
compensated by adding cysteine or relatively large numbers of 'splenic
adherent cells' to the culture. Elevated extracellular glutamate levels were also found to
reduce the capacity of murine macrophages, human blood monocytes, and murine fibroblastoid
cells (L929 cells) to release acid-soluble thiol (cysteine) into the
extracellular space. The three cell types differed, however, with respect to their
sensitivity against the three structural analogues of glutamate. The elevated glutamate
concentration was not non-specifically toxic for cultured macrophages, since glycolytic
activity and arginase activity were not inhibited. Implications of these observations for
the pathogenetic mechanism of AIDS are discussed.
- Language of Publication
- English
- Unique Identifier
- 91207935
- MeSH Heading (Major)
- Glutamates|*BL/PD; HIV Infections|*BL/IM; HIV-1|*
- MeSH Heading
- Cysteine|SE; Human; In Vitro; Lymphocyte Transformation|DE;
Lymphocytes|DE/IM; Macrophages|DE/IM/SE
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0953-8178
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 0 (Glutamates); 4371-52-2 (Cysteine); 56-86-0 (Glutamic Acid)
Record 108 from database: MEDLINE
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- Title
- Metabolic effects of acetaldehyde.
- Author
- Lieber CS
- Address
- Alcohol Research and Treatment Center, Veterans Administration Medical Center, Bronx,
New York.
- Source
- Biochem Soc Trans, 1988 Jun, 16:3, 241-7
- Abstract
- Acetaldehyde, the toxic product of ethanol metabolism in the liver, covalently binds to
a variety of proteins, thereby altering liver function and structure. Through its binding
to tubulin, acetaldehyde decreases the polymerization of microtubules thereby impairing
protein secretion and favouring their retention, with associated swelling of hepatocytes.
Acetaldehyde adduct formation also impairs some enzyme activities. Either directly or
through binding with GSH, acetaldehyde favours lipid peroxidation. Various mitochondrial
functions are altered, particularly after chronic ethanol consumption which sensitizes the
mitochondria to the toxic effects of acetaldehyde. In cultured myofibroblasts,
acetaldehyde stimulates collagen production. The acetaldehyde-protein adducts stimulate
the production of antibodies directed against the acetaldehyde epitope. This immune
response may contribute to the aggravation or perpetuation of alcohol-induced liver
damage. Some acetaldehyde effects, however, could conceivably be considered as beneficial,
such as the stimulation of vascular prostacyclin release which may take part in the
'protective' effect of moderate ethanol consumption against some cardiovascular
complications.
- Language of Publication
- English
- Unique Identifier
- 89031624
- MeSH Heading (Major)
- Acetaldehyde|BL/*ME
- MeSH Heading
- Alcoholism|ME; Cell Membrane|DE/ME; Cysteine|ME; Glutathione|ME; Human;
Intracellular Membranes|DE/ME; Iron|ME; Lipid Peroxidation; Mitochondria, Liver|DE/ME;
Protein Binding; Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-5127
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 4371-52-2 (Cysteine); 70-18-8 (Glutathione); 7439-89-6 (Iron); 75-07-0
(Acetaldehyde)
Record 109 from database: MEDLINE
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- Title
- A comparison of the protective effects of N-acetyl-cysteine and S-carboxymethylcysteine
against paracetamol-induced hepatotoxicity.
- Author
- Ioannides C; Hall DE; Mulder DE; Steele CM; Spickett J; Delaforge M; Parke DV
- Address
-
- Source
- Toxicology, 1983 Nov, 28:4, 313-21
- Abstract
- The protective effect of the sulphur-containing amino acids N-acetyl-cysteine and
S-carboxymethylcysteine against paracetamol-induced hepatotoxicity was evaluated in the
hamster by biochemical and histological methods. Of the animals receiving paracetamol
alone 25% died within 24 h following administration. All surviving animals showed acute
hepatocellular injury and marked loss of cytochrome P-450 and hepatic mixed-function
oxidase activities. Simultaneous administration of N-acetylcysteine decreased the
mortality rate, partly prevented the paracetamol-induced liver damage and partly restored
enzyme activities. Simultaneous administration of S-carboxymethylcysteine with paracetamol
afforded no protection. Kidneys from all animals were histologically normal. Human liver
microsomes and liver microsomes from 3-methylcholanthrene-pretreated hamsters metabolished
paracetamol to intermediate(s) that bind covalently to microsomal proteins. The rate of
covalent binding was inhibited markedly by N-acetylcysteine and to a lesser extent by
S-carboxylmethylcysteine.
- Language of Publication
- English
- Unique Identifier
- 84074084
- MeSH Heading (Major)
- Acetaminophen|*AI/ME/TO; Acetylcysteine|*PD; Carbocysteine|*PD; Cysteine|*AA;
Hepatitis, Toxic|PA/*PC
- MeSH Heading
- Animal; Comparative Study; Hamsters; Human; In Vitro; Kidney|DE/PA; Male; Mesocricetus;
Microsomes, Liver|DE/EN; Protein Binding|DE; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0300-483X
- Country of Publication
- NETHERLANDS
- CAS Registry/EC Number
- 103-90-2 (Acetaminophen); 2387-59-9 (Carbocysteine); 4371-52-2 (Cysteine);
616-91-1 (Acetylcysteine)
Record 110 from database: MEDLINE
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- Title
- Defective Rho GTPase regulation by IL-1 beta-converting enzyme-mediated cleavage of D4
GDP dissociation inhibitor.
- Author
- Danley DE; Chuang TH; Bokoch GM
- Address
- Department of Molecular Sciences, Pfizer Central Research, Groton, CT 06340, USA.
- Source
- J Immunol, 1996 Jul, 157:2, 500-3
- Abstract
- GTPases of the Rho family regulate many aspects of inflammatory cell activity, including
motility, formation of toxic oxygen metabolites, and generation of proinflammatory
cytokines. Defective regulation of such signaling pathways leads to a variety of acute and
chronic inflammatory disorders, although the mechanisms by which this occurs have not been
well defined. We describe in this work specific proteolytic cleavage of D4 GDI, a critical
regulator of Rho GTPase activity in inflammatory leukocytes, by IL-1 beta-converting
enzyme (ICE). Cleavage of D4 GDI by ICE occurs at Asp55, leading to the formation of the
truncated D4 that is unable to effectively bind and regulate GTPases of the Rho family.
Our data suggest that activation of ICE protease(s) at inflammatory sites leads to
defective Rho GTPase regulation. Release of these critical regulatory proteins may
contribute substantially to the inflammatory response at these sites, exacerbating and
perpetuating the resulting tissue damage.
- Language of Publication
- English
- Unique Identifier
- 96286022
- MeSH Heading (Major)
- Cysteine Proteinases|*ME/*PD; G-Proteins|AI/*DE/*ME; GTP
Phosphohydrolase|*ME
- MeSH Heading
- Amino Acid Sequence; Base Sequence; Cell Line; Human; Molecular Sequence Data;
Monocytes|EN; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0022-1767
- Country of Publication
- UNITED STATES
Record 111 from database: MEDLINE
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- Title
- Role of sulfhydryls in the hepatotoxicity of organic and metallic compounds.
- Author
- Klaassen CD; Bracken WM; Dudley RE; Goering PL; Hazelton GA; Hjelle JJ
- Address
-
- Source
- Fundam Appl Toxicol, 1985 Oct, 5:5, 806-15
- Abstract
- Endogenous sulfhydryl compounds serve a critical role in maintaining the function and
viability of living systems. Glutathione (GSH) is the most abundant of these nonprotein
thiols. During the past decade it has been demonstrated that sulfhydryls such as GSH also
serve an important role in protecting vital nucleophilic sites in the liver from
electrophilic attack by numerous classes of reactive chemicals. Organocompounds such as
bromobenzene and acetaminophen which undergo microsomal metabolism yield reactive
intermediates that are specifically inactivated by conjugation with sulfhydryls in the
form of GSH. Thus, for organocompounds GSH is extremely important in protecting against
toxic insults. More recently, other sulfhydryl compounds also have been found to serve a
specific but as yet less defined role in protecting biological systems against chemically
induced injury. Metals such as cadmium have a high affinity for sulfhydryls and the metal
binding protein metallothionein binds cadmium with high affinity. The highly specific
association of the metal with this sulfhydryl-enriched protein serves to effectively
sequester the reactive cadmium ion. The central role of sulfhydryl equivalents in the
detoxication of organo- and metallocompounds is similar; however, the mechanism by which
this is achieved is fundamentally different.
- Language of Publication
- English
- Unique Identifier
- 86056693
- MeSH Heading (Major)
- Hepatitis, Toxic|*ME; Metals|*TO; Sulfhydryl Compounds|*ME
- MeSH Heading
- Acetaminophen|TO; Animal; Biotransformation; Bromobenzenes|TO; Cadmium Poisoning|ME; Cysteine|PD;
Cytochrome P-450|ME; Human; Metallothionein|ME; Microsomes, Liver|EN; Support, U.S. Gov't,
P.H.S.; Zinc|TO
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 0272-0590
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Bromobenzenes); 0 (Metals); 0 (Sulfhydryl Compounds); 103-90-2 (Acetaminophen);
4371-52-2 (Cysteine); 7440-66-6 (Zinc); 9035-51-2 (Cytochrome P-450);
9038-94-2 (Metallothionein)
Record 112 from database: MEDLINE
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- Title
- Detection of free radicals in UV-irradiated lens by spin trapping ESR.
- Author
- Murakami J; Kozuka Y; Okazaki M; Shiga T
- Address
- Kozuka Eye Clinic, Ehime, Japan.
- Source
- Lens Eye Toxic Res, 1992, 9:3-4, 447-54
- Abstract
- We have made an ESR study on the UV-photolysis of lens and identified the origins of
free radicals involved in the initial photochemical process by spin trapping technique.
Two spin adducts were detected on irradiation of canine lens in the presence of a spin
trapping reagent (DMPO); a spin adduct of sulfur centered radical derived from glutathione
and the protonated adduct of hydrated electron. A free radical mechanism of initial
photochemical injury in UV-irradiated lens was discussed, comparing with a photolysis of
tryptophan plus cysteine solution.
- Language of Publication
- English
- Unique Identifier
- 93249979
- MeSH Heading (Major)
- Electron Spin Resonance Spectroscopy|*MT; Lens, Crystalline|ME/*RE
- MeSH Heading
- Animal; Cyclic N-Oxides|CYCLIC OXIDES N; Cysteine|RE; Dogs; Free
Radicals|RE; Human; Spin Labels; Tryptophan|RE; Ultraviolet Rays
- Publication Type
- JOURNAL ARTICLE
- ISSN
- 1042-6922
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Cyclic N-Oxides); 0 (Free Radicals); 0 (Spin Labels); 3317-61-1
(5,5-dimethyl-1-pyrroline-1-oxide); 4371-52-2 (Cysteine); 6912-86-3
(Tryptophan)
The
research reports which follow are referred to as REVIEW reports because they REVIEW many
other studies, rather than report on a new study.
Record 113 from database: MEDLINE
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- Title
- Biosynthesis and biotransformation of glutathione S-conjugates to toxic metabolites.
- Author
- Anders MW; Lash L; Dekant W; Elfarra AA; Dohn DR
- Address
- Department of Pharmacology, School of Medicine and Dentistry, University of Rochester,
New York.
- Source
- Crit Rev Toxicol, 1988, 18:4, 311-41
- Abstract
- The material presented in this review deals with the hypothesis that the nephrotoxicity
of certain halogenated alkanes and alkenes is associated with hepatic biosynthesis of
glutathione S-conjugates, which are further metabolized to the corresponding cysteine
S-conjugates. Some glutathione or cysteine S-conjugates may be
direct-acting nephrotoxins, but most cysteine S-conjugates require
bioactivation by renal, pyridoxal phosphate-dependent enzymes, such as cysteine
conjugate beta-lyase (beta-lyase). The biosynthesis of glutathione S-conjugates is
catalyzed by both the cytosolic and the microsomal glutathione S-transferases, although
the latter enzyme is a better catalyst for the reaction of haloalkenes with glutathione.
When glutathione S-conjugate formation yields sulfur mustards, as occurs with
vicinal-dihaloethanes, the S-conjugates are direct-acting toxins. In contrast, the
S-conjugates formed from fluoro- and chloroalkenes yield S-alkyl- or S-vinyl glutathione
conjugates, respectively, which are metabolized to the corresponding cysteine
S-conjugates by gamma-glutamyltransferase and dipeptidases; inhibition of these enzymes
blocks the toxicity of the glutathione S-conjugates. The cysteine
S-conjugates must be metabolized by beta-lyase for the expression of toxicity; the
beta-lyase inhibitor aminooxyacetic acid blocks the toxicity of cysteine
S-conjugates, and the corresponding alpha-methyl cysteine S-conjugates,
which cannot be metabolized by beta-lyase, are not toxic. Moreover, probenecid, an
inhibitor of renal anion transport system, blocks the toxicity of cysteine
S-conjugates, which cannot be metabolized by beta-lyase, are not toxic. Moreover,
probenecid, an inhibitor of renal anion transport system, blocks the toxicity of cysteine
S-conjugates. Homocysteine S-conjugates are also potent cyto- and nephrotoxins. The high
renal content of gamma-glutamyltransferase and the renal anion transport system are
probably determinants of kidney tissue as a target site. Biochemical studies indicate that
renal mitochondrial dysfunction is produced by the cysteine S-conjugates.
Finally, some of the glutathione and cysteine conjugates are mutagenic in
the Ames test, and reactive intermediates formed by the action of beta-lyase may
contribute to the nephrocarcinogenicity of certain chloroalkenes.
- Language of Publication
- English
- Unique Identifier
- 88242261
- MeSH Heading (Major)
- Carcinogens|*/PK; Glutathione Transferases|*ME
- MeSH Heading
- Animal; Biotransformation; Cells, Cultured; Chemistry; Human; Support, Non-U.S. Gov't;
Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 1040-8444
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 2.5.1.18 (Glutathione Transferases); 0 (Carcinogens)
Record 114 from database: MEDLINE
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- Title
- Mitochondrial bioactivation of cysteine S-conjugates and
4-thiaalkanoates: implications for mitochondrial dysfunction and mitochondrial diseases.
- Author
- Anders MW
- Address
- Department of Pharmacology, University of Rochester, New York 14642, USA.
- Source
- Biochim Biophys Acta, 1995 May, 1271:1, 51-7
- Abstract
- The toxicity of most drugs and chemicals is associated with their enzymatic conversion
to toxic metabolites. Bioactivation reactions occur in a range of organs and organelles,
including mitochondria. The toxicity of haloalkene-derived cysteine
S-conjugates and related 4-thiaalkanoates is associated with their mitochondrial
bioactivation. Toxic cysteine S-conjugates are formed by the glutathione
S-transferase-catalyzed addition of glutathione to haloalkenes to give glutathione
S-conjugates, which are hydrolyzed by gamma-glutamyltransferase and dipeptidases.
Mitochondrial cysteine conjugate beta-lyase-catalyzed bioactivation of cysteine
S-conjugates affords unstable alpha-halothiolates. Haloalkene-derived 4-thiaalkanoates,
which are analogs of cysteine S-conjugates that lack an alpha-amino
group, undergo bioactivation by the enzymes of fatty acid beta-oxidation to give
3-hydroxy-4-thiaalkanoates that eliminate alpha-halothiolates. alpha-Halothiolates yield
alkylating and acylating agents that interact with cellular macromolecules and thereby
cause cell damage. Mitochondrial dysfunction is the hallmark of cysteine
S-conjugate-induced cytotoxicity: decreased respiration, decreased ATP and total adenine
nucleotide concentrations, depletion of the mitochondrial glutathione content,
perturbations in cellular Ca2+ homeostasis, and damage to the mitochondrial genome are
seen with cysteine S-conjugates. Similar changes are observed with
cytotoxic 4-thiaalkanoates, but inhibition of the medium-chain acyl-CoA dehydrogenase and
hypoglycemia are also observed.
- Language of Publication
- English
- Unique Identifier
- 95322492
- MeSH Heading (Major)
- Cysteine|AA/*ME; Hydrocarbons, Halogenated|*ME/*TO; Mitochondria|*ME;
Mitochondrial Myopathies|*ME; Organelles|*ME
- MeSH Heading
- Animal; Biotransformation; Glutathione Transferase|ME; Human; Microsomes|ME; Oxidative
Phosphorylation|DE; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0006-3002
- Country of Publication
- NETHERLANDS
Record 115 from database: MEDLINE
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- Title
- Cellular effects of reactive intermediates: nephrotoxicity of S-conjugates of amino
acids.
- Author
- Anders MW; Elfarra AA; Lash LH
- Address
-
- Source
- Arch Toxicol, 1987, 60:1-3, 103-8
- Abstract
- Several cysteine S-conjugates are potent nephrotoxins and require
enzymatic activation to produce cytotoxicity. Strategies based on the knowledge that renal
cysteine conjugate beta-lyase is apparently a pyridoxal phosphate
(PLP)-dependent enzyme have been exploited to test the hypothesis that a
beta-lyase-dependent activation is required for the expression of cysteine
S-conjugate-induced toxicity. First, the toxicity of the model conjugate
S-(1,2-dichlorovinyl)-L-cysteine (DCVC) is blocked both in vivo and in
isolated, renal proximal tubular cells by aminooxyacetic acid, an inhibitor of
PLP-dependent enzymes. Second, the nonmetabolizable alpha-methyl analogue
S-(1,2-dichlorovinyl)-DL-alpha-methylcysteine is not toxic. Third, to test the hypothesis
that the toxicity of DCVC is associated with the metabolic formation of a reactive thiol,
S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC), which may undergo a PLP-dependent
gamma-elimination reaction to produce an identical thiol, was studied. DCVHC is a potent
nephrotoxin, and, similar to DCVC, its toxicity was blocked by aminooxyacetic acid and the
alpha-methyl analogue S-(1,2-dichlorovinyl)-DL-alpha-methylhomocysteine was not toxic.
Moreover, exposure of renal proximal tubular cells to propargylglycine, a suicide
substrate for PLP-dependent enzymes that catalyze gamma-elimination reactions, blocked the
toxicity of DCVHC. Fourth, the renal mitochondrial beta-lyase is localized in the outer
membrane; therefore, although DCVC was toxic to mitochondria, no toxicity was produced in
mitoplasts, which shows that a suborganelle site of activation is involved in the
mitochondrial toxicity of DCVC. Finally, the toxicity of both DCVC and DCVHC was blocked
by probenecid, indicating a role for the anion transport system. DCVC and DCVHC inhibit
cellular and mitochondrial respiration, indicating that mitochondria are primary
intracellular targets for nephrotoxic S-conjugates.(ABSTRACT TRUNCATED AT 250 WORDS)
- Language of Publication
- English
- Unique Identifier
- 87297915
- MeSH Heading (Major)
- Amino Acids|*TO; Cell Survival|*DE; Kidney Diseases|*CI
- MeSH Heading
- Animal; Cysteine|TO; Human; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0340-5761
- Country of Publication
- GERMANY, WEST
- CAS Registry/EC Number
- 0 (Amino Acids); 4371-52-2 (Cysteine)
Record 116 from database: MEDLINE
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- Title
- Glutathione conjugate mediated toxicities.
- Author
- Monks TJ; Anders MW; Dekant W; Stevens JL; Lau SS; van Bladeren PJ
- Address
- Division of Pharmacology and Toxicology, College of Pharmacy, University of Texas,
Austin 78712.
- Source
- Toxicol Appl Pharmacol, 1990 Oct, 106:1, 1-19
- Abstract
- Glutathione (gamma-glutamyl-L-cysteinylglycine: GSH) is present in high concentrations
in most living cells and participates in a variety of vital cellular reactions. In
particular, GSH protects cells from potentially toxic electrophiles formed via the
metabolism of xenobiotics, and such reactions have long been associated with the process
of detoxication (Baumann and Preusse, 1879; Jaffe, 1879). Compounds that form GSH
conjugates are processed by gamma-glutamyl transpeptidase (gamma-GT) and dipeptidases to cysteine
S-conjugates, which are usually excreted in urine as their corresponding mercapturic acids
(S-substituted N-acetyl-L-cysteine conjugates). In addition, GSH
peroxidase activity, whether catalyzed by the selenium-dependent GSH peroxidase or by the
GSH S-transferases, serves to detoxify hydrogen peroxide and organic hydroperoxides.
However, in recent years, evidence indicating that GSH conjugation plays an important role
in the formation of toxic metabolites from a variety of chemicals has accumulated. Thus,
several classes of compounds are converted, via conjugation with GSH, into either
cytotoxic, genotoxic, or mutagenic metabolites. The purposes of the symposium on
"Glutathione Conjugate Mediated Toxicities" presented at the 1990 Society of
Toxicology Annual Meeting were to discuss recent findings in this rapidly moving field, to
present ideas on the mechanisms and modulation of GSH conjugate-dependent toxicities, to
present a consensus on the broader significance of this work, and to identify directions
for future research. This paper summarizes these presentations. GSH conjugation reactions
are involved in the bioactivation of several classes of xenobiotics, and four types of
GSH-dependent bioactivation reactions can be identified: (1) directly toxic GSH conjugates
may be formed from vicinal dihaloalkanes via formation of electrophilic sulfur mustards;
(2) cysteine conjugate beta-lyase-dependent bioactivation is involved in
the selective nephrotoxicity of haloalkenes; (3) GSH conjugates of hydroquinones and
isothiocyanates may serve as transport and targeting metabolites; and (4) GSH-dependent
reactions may be involved in the release of toxic agents from precursor organic
thiocyanates and nitrosoguanidines (N-methyl-N'-nitro-N-nitroguanidine).
- Language of Publication
- English
- Unique Identifier
- 91068229
- MeSH Heading (Major)
- Glutathione|*ME
- MeSH Heading
- Animal; Biotransformation; Carcinogens|ME; Human; Kidney|ME; Liver|ME; Lyases|PH;
Mutagens|ME; Organ Specificity; Quinones|ME; Support, Non-U.S. Gov't; Support, U.S. Gov't,
Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0041-008X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 4. (Lyases); EC 4.4.1.6 (S-alkylcysteine lyase); 0 (Carcinogens); 0 (Mutagens); 0
(Quinones); 70-18-8 (Glutathione)
Record 117 from database: MEDLINE
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- Title
- Collagenase inhibitors: rationale for their use in treating corneal ulceration.
- Author
- Berman
- Address
-
- Source
- Int Ophthalmol Clin, 1975 Winter, 15:4, 49-66
- Abstract
- Tissue collagenases have been implicated in corneal ulceration in human corneal disease
and in ulceration of the rabbit cornea that has served as a model system. Such enzymes
from the rabbit and human cornea are inhibited by metal-binding agents of the EDTA type,
by thiols, and by the human serum antiprotease alpha2-macroglobulin. Determination of the
relative efficacies of collagenase inhibitors indicates that EDTA and Ca-EDTA are about
one hundred times more effective on a molar basis than L-cysteine and its
derivatives, N-acetyl-L-cysteine and D-penicillamine. The
alpha2-macroglobulin on a molar basis, is superior as an inhibitor to the metal-binding
agents and thiols. Although Ca may be a necessary cofactor of the corneal collagenases,
such a requirement has not been established unequivocally. Inhibition and isotope studies
do indicate a requirement for Zn. Thiols are thought to inhibit corneal collagenases by
binding to or removing an intrinsic metal cofactor (Zn), and/or possibly by reducing one
or more disulfide bonds. Inhibition by both EDTA-type agents and thiols is largely
reversible by dialysis. The human alpha2-macroglobulin appears to inhibit corneal
colleagenases irreversibly by forming tight complexes with them. Ca-EDTA, cysteine,
and acetylcysteine, given as eyedrops, are able to prevent or retard ulceration in the
alkali-burned rabbit cornea. They appear to have some efficacy in the prevention of
corneal ulceration in humans. EDTA-type compounds are quite stable under routine storage,
while acetylcysteine is more stable than cysteine. EDTA is quite toxic
and should not be used as eye medication. Ca-EDTA has a low toxicity, and cysteine
and acetylcysteine have even lower toxicity. It is not yet certain which inhibitor has the
most favorable therapeutic index for clinical use, or is the optimal mode of drug delivery
known. However, the collagenase inhibitors seem to have therapeutic promise in the
prevention of corneal ulceration.
- Language of Publication
- English
- Unique Identifier
- 76189571
- MeSH Heading (Major)
- Corneal Ulcer|*DT; Microbial Collagenase|*AI/ME
- MeSH Heading
- alpha 1-Antitrypsin|TU; alpha-Macroglobulins|TU; Acetylcysteine|AE/TU; Animal;
Calcium|AE/ME/TU; Cyclic AMP|PH;
Record 118
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- Title
- Memories of metallothionein.
- Author
- Kille P; Hemmings A; Lunney EA
- Address
- Department of Biochemistry, University of Wales College of Cardiff, Wales, UK.
- Source
- Biochim Biophys Acta, 1994 Apr, 1205:2, 151-61
- Abstract
- Metallothionein (MT) has provided nature with a small molecule which exhibits multiple
facets. The distinct arrangement of cysteine residues which occurs within the two domains
of MT confers predisposed metal specificity upon each domain. Furthermore, subtle changes
in primary sequence may be built onto the metal cluster scaffold. These not only bestow
immunodistinction but may also potentially allow specific members of this family such as
MT-III to fulfill unique biological roles. An understanding of how the structures of MT
molecules predetermine their biochemical characteristics may allow the design of novel
metal-binding molecules specific for the metal ion of choice. Already, using nature as a
blueprint, a semi-specific cadmium-binding molecule has been constructed from a polymer of
mammalian C-terminal domains. This novel protein has been used to protect tobacco plants
from cadmium toxicity. In addition, modeling of biologically active determinants which are
located on the external face of MT-III may facilitate the design of small synthetic
molecules which mimic the biological activity of MT-III and prevent the distressing
effects of memory and speech loss associated with Alzheimer's disease. Memories of
metallothionein may yet be something worth remembering!
- Language of Publication
- English
- Unique Identifier
- 94206989
- MeSH Heading (Major)
- Chelating Agents|CH/*ME; Metallothionein|CH/GE/IM/*ME; Metals|*ME
- MeSH Heading
- Amino Acid Sequence; Animal; Brain Chemistry; Human; Molecular Sequence Data; Support,
Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0006-3002
- Country of Publication
- NETHERLANDS
Record 119 from database: MEDLINE
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- Title
- Farnesyltransferase as a target for anticancer drug design.
- Author
- Qian Y; Sebti SM; Hamilton AD
- Address
- Department of Chemistry and Pharmacology, University of Pittsburgh, PA 15215, USA.
- Source
- Biopolymers, 1997, 43:1, 25-41
- Abstract
- The currently understood function for Ras in signal transduction is in mediating the
transmission of signals from external growth factors to the cell nucleus. Mutated forms of
this GTP-binding protein are found in 30% of human cancers with particularly high
prevalence in colon and pancreatic carcinomas. These mutations destroy the GTPase activity
of Ras and cause the protein to be locked in its active, GTP bound form. As a result, the
signaling pathways are activated, leading to uncontrolled tumor growth. Ras function in
signaling requires its association with the plasma membrane. This is achieved by
posttranslational farnesylation of a cysteine residue present as part of the CA1A2X
carboxyl terminal tetrapeptide of all Ras proteins. The enzyme that recognizes and
farnesylates the CA1A2X sequence, Ras farnesyltransferase (FTase), has become an important
target for the design of inhibitors that might be interesting as antitumor agents. Several
approaches have been taken in the search for in vivo active inhibitors of
farnesyltransferase. These include the identification of natural products such as the
chaetomellic and zaragozic acids that mimic farnesylpyrophosphate, bisubstrate transition
state analogs combining elements of the farnesyl and tetrapeptide substrates and
peptidomimetics that reproduce features of the carboxyl terminal tetrapeptide CA1A2X
sequence. This last group of compounds has been most successful in showing highly potent
inhibition of FTase and selective blocking of Ras processing in a range of Ras transformed
tumor cell lines at concentrations as low as 10 nM. Certain peptidomimetics will also
block tumor growth in various mouse models, with apparently few toxic side effects. These
results suggest that farnesyltransferase inhibitors hold considerable promise as
anticancer drugs in the clinic.
- Language of Publication
- English
- Unique Identifier
- 97317383
- MeSH Heading (Major)
- Antineoplastic Agents|*PD; Transferases|*DE
- MeSH Heading
- Amino Acid Sequence; Animal; Drug Design; Human; Molecular Sequence Data; Support, U.S.
Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0006-3525
- Country of Publication
- UNITED STATES
Record 120 from database: MEDLINE
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- Title
- Farnesyltransferase inhibitors and anti-Ras therapy.
- Author
- Gibbs JB; Kohl NE; Koblan KS; Omer CA; Sepp Lorenzino L; Rosen N; Anthony NJ; Conner MW;
deSolms SJ; Williams TM; Graham SL; Hartman GD; Oliff A
- Address
- Department of Cancer Research, Merck Research Laboratories, West Point, PA 19486, USA.
- Source
- Breast Cancer Res Treat, 1996, 38:1, 75-83
- Abstract
- The oncoprotein encoded by mutant ras genes is initially synthesized as a cytoplasmic
precursor which requires posttranslational processing to attain biological activity;
farnesylation of the cysteine residue present in the CaaX motif located at the
carboxy-terminus of all Ras proteins is the critical modification. Once farnesylated and
further modified, the mature Ras protein is inserted into the cell's plasma membrane where
it participates in the signal transduction pathways that control cell growth and
differentiation. The farnesylation reaction that modifies Ras and other cellular proteins
having an appropriate CaaX motif is catalyzed by a housekeeping enzyme termed
farnesyl-protein transferase (FPTase). Inhibitors of this enzyme have been prepared by
several laboratories in an effort to identify compounds that would block Ras-induced cell
transformation and thereby function as Ras-specific anticancer agents. A variety of
natural products and synthetic organic compounds were found to block farnesylation of Ras
proteins in vitro. Some of these compounds exhibit antiproliferative activity in cell
culture, block the morphological alterations associated with Ras-transformation, and can
block the growth of Ras-transformed cell lines in tumor colony-forming assays. By
contrast, these compounds do not affect the growth or morphology of cells transformed by
the Raf or Mos oncoproteins, which do not require farnesylation to achieve biological
activity. The efficacy and lack of toxicity observed with FPTase inhibitors in an animal
tumor model suggest that specific FPTase inhibitors may be useful for the treatment of
some types of cancer.
- Language of Publication
- English
- Unique Identifier
- 96422508
- MeSH Heading (Major)
- ras Proteins|*AI; Antineoplastic Agents|*PD; Enzyme Inhibitors|*PD; Transferases|*AI
- MeSH Heading
- Animal; Guanosine Triphosphate|ME; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0167-6806
- Country of Publication
- NETHERLANDS
Record 121 from database: MEDLINE
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- Title
- Protein-alkali reactions: chemistry, toxicology, and nutritional consequences.
- Author
- Friedman M; Gumbmann MR; Masters PM
- Address
-
- Source
- Adv Exp Med Biol, 1984, 177:, 367-412
- Abstract
- Heat and alkali treatment of proteins catalyzes formation of crosslinked amino-acid side
chains such as lysinoalanine, ornithino-alanine and lanthionine, and concurrent
racemization of L-isomers of all amino acid residues to D-analogues. Factors that favor
these transformations include high pH and temperature, long exposure, and certain
inductive or steric properties of the various amino acid side chains. Factors that
minimize crosslink formation include the presence of certain additives, such as cysteine
or sulfite ions, and acylation of epsilon-NH2 groups of lysine side chains. Free and
protein-bound lysinoalanine and D-serine induce nephrocytomegaly in rat kidney tissues.
The presence of lysinoalanine and D-amino acid residues along a protein chain decreases
its digestibility and nutritional quality. Understanding the factors that govern the
formation of potentially harmful unnatural amino acid residues in food proteins and the
toxic and nutritionally antagonistic action of these compounds in animals should lead to
better and safer foods.
- Language of Publication
- English
- Unique Identifier
- 85043300
- MeSH Heading (Major)
- Dietary Proteins|*AE/ME; Food Handling|*; Nutrition|*
- MeSH Heading
- Alkalies; Animal; Caseins|AN; Cysteine|PD; Glucose|PD; Human; Hydrogen-Ion
Concentration; Kidney|DE; Lysinoalanine|AN/ME/TO; Molecular Conformation; Stereoisomerism;
Structure-Activity Relationship; Temperature; Time Factors
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0065-2598
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Alkalies); 0 (Caseins); 0 (Dietary Proteins); 18810-04-3 (Lysinoalanine); 4371-52-2
(Cysteine); 50-99-7 (Glucose)
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0020-8167
- Country of Publication
- UNITED STATES
Record 122 from database: MEDLINE
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- Title
- Consideration of the target organ toxicity of trichloroethylene in terms of metabolite
toxicity and pharmacokinetics.
- Author
- Davidson IW; Beliles RP
- Address
- Bowman Gray School of Medicine, Department of Pharmacology, Winston-Salem, NC 27103.
- Source
- Drug Metab Rev, 1991, 23:5-6, 493-599
- Abstract
- Trichloroethylene (TRI) is readily absorbed into the body through the lungs and
gastrointestinal mucosa. Exposure to TRI can occur from contamination of air, water, and
food; and this contamination may be sufficient to produce adverse effects in the exposed
populations. Elimination of TRI involves two major processes: pulmonary excretion of
unchanged TRI and relatively rapid hepatic biotransformation to urinary metabolites. The
principal site of metabolism of TRI is the liver, but the lung and possibly other tissues
also metabolize TRI, and dichlorovinyl-cysteine (DCVC) is formed in the
kidney. Humans appear to metabolize TRI extensively. Both rats and mice also have a
considerable capacity to metabolize TRI, and the maximal capacities of the rat versus the
mouse appear to be more closely related to relative body surface areas than to body
weights. Metabolism is almost linearly related to dose at lower doses, becoming dose
dependent at higher doses, and is probably best described overall by Michaelis-Menten
kinetics. Major end metabolites are trichloroethanol (TCE), trichloroethanol-glucuronide,
and trichloroacetic acid (TCA). Metabolism also produces several possibly reactive
intermediate metabolites, including chloral, TRI-epoxide, dichlorovinyl-cysteine
(DCVC), dichloroacetyl chloride, dichloroacetic acid (DCA), and chloroform, which is
further metabolized to phosgene that may covalently bind extensively to cellular lipids
and proteins, and, to a much lesser degree, to DNA. The toxicities associated with TRI
exposure are considered to reside in its reactive metabolites. The mutagenic and
carcinogenic potential of TRI is also generally thought to be due to reactive intermediate
biotransformation products rather than the parent molecule itself, although the biological
mechanisms by which specific TRI metabolites exert their toxic activity observed in
experimental animals and, in some cases, humans are not known. The binding intensity of
TRI metabolites is greater in the liver than in the kidney. Comparative studies of
biotransformation of TRI in rats and mice failed to detect any major species or strain
differences in metabolism. Quantitative differences in metabolism across species probably
result from differences in metabolic rate and enterohepatic recirculation of metabolites.
Aging rats have less capacity for microsomal metabolism, as reflected by covalent binding
of TRI, than either adult or young rats. This is likely to be the same in other species,
including humans. The experimental evidence is consistent with the metabolic pathways for
TRI being qualitatively similar in mice, rats, and humans. The formation of the major
metabolites--TCE, TCE-glucuronide, and TCA--may be explained by the production of chloral
as an intermediate after the initial oxidation of TRI to TRI-epoxide.(ABSTRACT TRUNCATED
AT 400 WORDS)
- Language of Publication
- English
- Unique Identifier
- 92201111
- MeSH Heading (Major)
- Trichloroethylene|PK/*TO
- MeSH Heading
- Animal; Human; Organ Specificity; Support, U.S. Gov't, Non-P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0360-2532
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 79-01-6 (Trichloroethylene)
Record 123 from database: MEDLINE
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- Title
- Kinetics and metabolism of paracetamol and phenacetin.
- Author
- Prescott LF
- Address
-
- Source
- Br J Clin Pharmacol, 1980 Oct, 10 Suppl 2:, 291S-298S
- Abstract
- 1 The rate of absorption of oral paracetamol depends on the rate of gastric emptying and
is usually rapid and complete. The mean systemic availability is about 75%. 2 Paracetamol
is extensively metabolized and the plasma half-life is 1.5-2.5 hours. About 55% and 30% of
a therapeutic dose is excreted in the urine as glucuronide and sulphate conjugates,
respectively, whereas mercapturic acid and cysteine conjugates
(representing conversion to a potentially toxic intermediate metabolite) each account for
some 4% of the dose. Paracetamol metabolism is age- and dose-dependent. 3 With hepatotoxic
doses, paracetamol metabolism is impaired and the half-life prolonged. Sulphate
conjugation is saturated and the proportion excreted as mercapturic acid and cysteine
conjugates is increased. 4 The renal clearance of paracetamol depends on urine flow rate
by not pH. The renal clearances of the glucuronide and sulphate conjugates often exceed
the glomerular filtration rate and are independent of urine flow and pH. 5 Phenacetin
absorption depends on formulation. It is extensively metabolized to paracetamol and minor
metabolites are probably responsible for toxicity.
- Language of Publication
- English
- Unique Identifier
- 81062967
- MeSH Heading (Major)
- Acetaminophen|AD/*ME; Phenacetin|AE/*ME
- MeSH Heading
- Administration, Oral; Adult; Animal; Biotransformation; Human; Intestinal Absorption;
Kinetics; Metabolic Clearance Rate; Tissue Distribution
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0306-5251
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 103-90-2 (Acetaminophen); 62-44-2 (Phenacetin)
Record 124 from database: MEDLINE
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- Title
- Dynamics of melanogenesis intermediates.
- Author
- Pavel S
- Address
- Department of Dermatology, University Hospital, Leiden, The Netherlands.
- Source
- J Invest Dermatol, 1993 Feb, 100:2 Suppl, 162S-165S
- Abstract
- The course of melanogenesis in (malignant) melanocytes is determined by several
relatively independent metabolic processes such as tyrosine uptake and compartmentation,
the activity of tyrosinase, and the capacity of melanosomes to produce and store melanin.
There is experimental evidence that tyrosine is transported across the cell membrane with
a Na(+)-independent L transport system. Tyrosine designated for melanogenesis is probably
localized in compartments different from those for protein synthesis. The maturation and
subsequent activation of tyrosinase occurs primarily in the Golgi-associated endoplasmatic
reticulum and coated vesicles. In these locations, the interaction between tyrosine and
tyrosinase has some limitations because no melanin polymer can be detected in these
structures. Nevertheless, the coated vesicles were shown to contain unpolymerized
monomeric indols. Individual skin types differ in their ability to produce mature, fully
pigmented, melanosomes. Whereas eumelanin content in melanocytes corresponds to the
phenotypic appearance of the skin, the formation of pheomelanin varies considerably.
Precursors of pheomelanin, such as glutathione and cysteine, are
responsible for scavenging potentially toxic quinoid products of melanogenesis that escape
from melanogenic compartments. Pheomelanogenesis can therefore be considered as one of the
protective mechanisms of melanocytes. Significant leakage of reactive intermediates of
melanogenesis may occur from aberrant melanosomes and explain the frequent incidence of
necrosis in melanoma tissue. The presence of O-methylated derivatives of
5,6-dihydroxyindole (5,6DHI) and 5,6-dihydroxyindole-2-carboxylic acid (5,6DHI2C) in
medium of melanoma cell cultures gives evidence of intracellular O-methylating ability.
The O-methylation of o-dihydroxyphenols and indols by catechol-O-methyltransferase
localized in microsomes and cytoplasma prevents their oxidation to reactive quinones. It
is suggested, however, that this protective mechanism can be unreliable because
catechol-O-methyltransferase can be inactivated by its oxidated substrates.
- Language of Publication
- English
- Unique Identifier
- 93163620
- MeSH Heading (Major)
- Melanins|*BI
- MeSH Heading
- Biological Transport; Catechol Methyltransferase|AI; Human; Indoles|ME; Melanocytes|ME;
Monophenol Monooxygenase|ME; Tyrosine|PK
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0022-202X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 1.14.18.1 (Monophenol Monooxygenase); EC 2.1.1.6 (Catechol Methyltransferase); 0
(Indoles); 0 (Melanins); 3131-52-0 (5,6-dihydroxyindole); 4790-08-3
(5,6-dihydroxy-2-indolylcarboxylic acid); 55520-40-6 (Tyrosine)
Record 125 from database: MEDLINE
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- Title
- Drug interactions affecting analgesic toxicity.
- Author
- Prescott LF; Critchley JA
- Address
-
- Source
- Am J Med, 1983 Nov 14, 75:5A, 113-6
- Abstract
- Most reports of interactions involving analgesics deal with their effects on the actions
of other drugs rather than vice versa. Aspirin and ethanol have synergistic effects on the
development of gastritis, gastrointestinal bleeding, and chronic gastric ulcer. This must
be the most common and most important interaction affecting analgesic toxicity. Combined
overdosage of aspirin with central nervous system depressants may be particularly
hazardous because suppression of the salicylate-induced respiratory stimulation further
shifts the disordered acid-base balance towards acidosis. The toxicity of acetaminophen
(paracetamol) depends primarily on the balance between the rate of formation of the
hepatotoxic metabolite and the rate of glutathione synthesis in the liver. In animals,
prolonged pretreatment with ethanol increases the metabolic activation and acute toxicity
of acetaminophen, and there is some evidence that chronic alcoholics are more susceptible
to hepatotoxicity following acute overdosage. It has been assumed that this sensitivity in
chronic alcoholics is due to microsomal enzyme induction with enhanced metabolic
activation of acetaminophen. However, the metabolic activation of acetaminophen, as judged
by the urinary excretion of its cysteine and mercapturic acid conjugates,
is not increased in heavy drinkers or in patients induced by long-term treatment with
anticonvulsants or rifampicin. Microsomal enzyme induction is complex. There are important
species differences and different agents may selectively induce different variants of the
multiple forms of cytochrome P-450. The acute administration of ethanol greatly reduces
the metabolic activation of acetaminophen in heavy drinkers with more than a 50 percent
decrease in cysteine and mercapturic acid conjugate production. Thus
ingestion of ethanol should reduce the risk of liver damage following acetaminophen
overdosage. Cimetidine, which inhibits the oxidative metabolism of some drugs, reduces the
hepatotoxicity and increases the dose of acetaminophen in mice required to kill 50 percent
of the animals. However, contrary to expectations, cimetidine does not inhibit the
oxidative metabolism of acetaminophen in man. Salicylamide competes with acetaminophen for
sulphate conjugation but is unlikely to potentiate toxicity following overdosage since
sulphate conjugation is rapidly saturated anyway. Animal studies suggest that the
hepatotoxicity of acetaminophen after overdosage may be increased by other agents which
deplete glutathione, but there is no information on this point in man.
- Language of Publication
- English
- Unique Identifier
- 84077049
- MeSH Heading (Major)
- Anti-Inflammatory Agents, Non-Steroidal|*AE
- MeSH Heading
- Acetaminophen|AE/PO; Alcohol, Ethyl|AE; Alcoholic Intoxication|CO; Alcoholism|ME;
Animal; Drug Interactions; Human; Liver Diseases|CI; Salicylates|AE/PO
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0002-9343
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Salicylates); 103-90-2 (Acetaminophen); 64-17-5 (Alcohol, Ethyl)
Record 126 from database: MEDLINE
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- Title
- Determination of mercapturic acid excretions in exposure control to toxicants.
- Author
- Nelson E
- Address
- Toxicology Laboratory, University Medical Center, Essen, Germany.
- Source
- Crit Rev Toxicol, 1992, 22:5-6, 371-89
- Abstract
- Toxicants can be converted in vivo by a variety of biotransformation reactions into
substances that are more, equally, or less noxious than the parent compound. Although
conjugation with glutathione is a process that usually results in less harmful products,
these products might subsequently form new metabolites that exert more toxicity than the
parent compound. These conjugation reactions are catalyzed by several classes of
glutathione-S-transferase isoenzymes and thus result in the urinary or biliary excretion
of N-acetyl-L-cysteine-S-conjugates (mercapturic acids). Inasmuch as
GSH-S-transferase activity varies among different tissues, urinary excretion of
mercapturic acids might reflect tissue-specific toxicity. Urinary mercapturic acids are
biomarkers of internal and, in some cases, effective dose. The utility of these markers
is, however, limited to times shortly after exposure. Studies on possible human
deficiencies in some GSH-S-transferases might help us better understand interindividual
variations in susceptibility to different toxicants and thus the differences in the
pathway of mercapturic acid excretion pattern.
- Language of Publication
- English
- Unique Identifier
- 93143853
- MeSH Heading (Major)
- Acetylcysteine|*UR; Xenobiotics|PK/*TO/UR
- MeSH Heading
- Animal; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 1040-8444
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Xenobiotics); 616-91-1 (Acetylcysteine)
Record 127 from database: MEDLINE
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- Title
- Role of renal metabolism in risk to toxic chemicals.
- Author
- Lash LH
- Address
- Department of Pharmacology, Wayne State University, School of Medicine, Detroit,
Michigan 48201, USA.
- Source
- Environ Health Perspect, 1994 Dec, 102 Suppl 11:, 75-9
- Abstract
- The kidneys are capable of carrying out extensive oxidation, reduction, hydrolysis, and
conjugation reactions. Renal cortex has high activities of cytochrome P450 and glutathione
(GSH) S-transferase. In contrast, renal medulla has high activity of prostaglandin
synthetase, which can catalyze co-oxidation of xenobiotics. While these pathways are found
in many tissues and at higher activities than in kidney, several key enzymes of the
mercapturic acid pathway are found at especially high activities in cells of the renal
proximal tubule. Investigations over the last two decades demonstrated that GSH
conjugation is not only a mechanism for detoxification of reactive electrophiles. Rather,
metabolism of GSH S-conjugates to the corresponding cysteine S-conjugates
represents a branch point: cysteine S-conjugates may be metabolized by
the cysteine S-conjugate N-acetyl-transferase to mercapturic acids, which
are nontoxic and are excreted, or they may be substrates for the pyridoxal
phosphate-dependent cysteine conjugate beta-lyase, which catalyzes either
a beta-elimination or a transamination reaction to produce unstable thiols. These thiols
rearrange to form potent acylating species that can covalently bind to cellular
macromolecules, thereby producing cytotoxicity, mutagenicity, and carcinogenicity. In
addition to the beta-lyase, two other renal enzymes, L-2-amino (2-hydroxy) acid oxidase
and cysteine conjugate S-oxidase, can bioactivate chemicals to produce
nephrotoxic species. Several halogenated alkanes and alkenes are bioactivated by these
pathways. These findings show that mammalian kidney is highly active in bioactivation of
xenobiotics. Although the properties of the corresponding enzymes in humans may differ, it
is clear that renal metabolism can be a critical determinant of risk to chemical injury.
- Language of Publication
- English
- Unique Identifier
- 95255145
- MeSH Heading (Major)
- Kidney|*DE/*ME; Xenobiotics|*ME
- MeSH Heading
- Animal; Glutathione|ME; Human; Lyases|ME; Metabolic Detoxication, Drug; Risk Assessment
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0091-6765
- Country of Publication
- UNITED STATES
Record 128 from database: MEDLINE
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- Title
- Metallothionein in physiological and physiopathological processes.
- Author
- Moffatt P; Denizeau F
- Address
- DÆepartement de Pharmacologie, FacultÆe de MÆedicine, UniversitÆe de MontrÆeal,
Succ. Centre-Ville, QuÆebec, Canada.
- Source
- Drug Metab Rev, 1997 Feb, 29:1-2, 261-307
- Abstract
- The multipurpose nature of MT that we have presented in this review has drawn attention
from many different fields of research: biochemistry, molecular biology, toxicology,
pharmacology, etc. In recent years, considerable advances have been made concerning the
regulation of MT genes by metals. Little, however, is known at the molecular level about
the mechanisms of MT induction by nonmetallic inducers such as growth factors. This is of
particular interest since MT is highly expressed during liver regeneration, an event
orchestrated by a series of growth stimulators and inhibitors. The significance of the
nuclear distribution of MT in growing cells and what controls its translocation are
questions that remain unanswered at the present time. The possibility that MT could
participate in a DNA synthesis-related process through donation or abstraction of Zn to
and from transcription factors has been inferred from in vitro studies. Such transfer
mechanisms, however, have yet to be confirmed in vivo. Overexpression of MT is often
accompanied by increased resistance towards a variety of alkylating agents and
chemotherapeutic drugs. The mechanisms by which MT protects cells against these agents may
depend on their distinct mode of toxic action. For some, MT cysteines can
be the target of the direct attack from the parent compound. For others such as
N-methyl-N-nitroso compounds, MT cysteines may serve as a sink for the
reactive oxygen species now known to be derived from their metabolism. In either case, a
primary consequence of such interactions is the release of the metals initially bound to
MT. Therefore, the metal composition of MT appears to be an important factor to consider
in determining the overall effect of MT in the resistance process.
- Language of Publication
- English
- Unique Identifier
- 97331190
- MeSH Heading (Major)
- Metallothionein|BI/GE/ME/*PH
- MeSH Heading
- Amino Acid Sequence; Animal; Human; Molecular Sequence Data
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0360-2532
- Country of Publication
- UNITED STATES
Record 129 from database: MEDLINE
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- Title
- Role of metallothionein in carcinogenesis.
- Author
- Cherian MG; Howell SB; Imura N; Klaassen CD; Koropatnick J; Lazo JS; Waalkes MP
- Address
- Department of Pathology, University of Western Ontario, London, Canada.
- Source
- Toxicol Appl Pharmacol, 1994 May, 126:1, 1-5
- Abstract
- Metallothionein (MT) is a low-molecular-weight protein (6800 Da) and one-third of its
amino acids are cysteine residues. The 20 cysteines coordinate 7 metal
atoms (zinc, copper, and/or cadmium). This protein is extremely inducible by metals as
well as a number of organic compounds. MT is though to be an important intracellular
storage site for zinc and possibly other essential trace elements. In addition, tolerance
to cadmium toxicity is often due to the induction of MT, which sequesters cadmium and
lowers its concentration at critical intracellular sites. Recently it has been proposed
that MT might play important roles in several aspects of the carcinogenic process. In this
context a symposium was held recently on this topic at the 1993 Annual Society of
Toxicology Meeting. At this symposium Dr. Cherian discussed the expression of MT in
various human tumors and its use as a potential marker of tumor differentiation or cell
proliferation. Dr. Imura provided data illustrating that induction of MT can be used as an
adjunct in cancer chemotherapy, in preventing toxicity caused by gamma-irradiation or
cisplatin (CDDP) and other chemotherapeutics. Induction of MT has been suggested to be an
important mechanism of resistance of tumor cells to chemotherapeutic agents, such as CDDP.
This is controversial, and various views on this topic were presented by Drs. Howell,
Lazo, and Koropatnick. Dr. Waalkes then discussed the role of MT in the carcinogenic and
anticarcinogenic effects of metals.
- Language of Publication
- English
- Unique Identifier
- 94240682
- MeSH Heading (Major)
- Metallothionein|*PH; Neoplasm Proteins|*PH; Neoplasms|DT/*ME
- MeSH Heading
- Animal; Antineoplastic Agents|PD; Cadmium|TO; Carcinogens|TO; Drug Resistance; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0041-008X
- Country of Publication
- UNITED STATES
Record 130 from database: MEDLINE
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- Title
- Regulation of metallothionein gene expression.
- Author
- Andrews GK
- Address
- Department of Biochemistry and Molecular Biology, University of Kansas Medical Center,
Kansas City 66103.
- Source
- Prog Food Nutr Sci, 1990, 14:2-3, 193-258
- Abstract
- The metallothioneins are small, cysteine-rich proteins that have the
capacity for high affinity binding of heavy metal ions, and whose synthesis is regulated
by metal ion concentrations. These properties suggest that they play pivotal roles in the
metabolism of the relatively nontoxic essential metals (zinc and copper), as well as toxic
heavy metals (cadmium), a concept supported by a variety of studies of cells in culture,
as well as in intact animals. Expression of the metallothionein genes may have important
implications in the nutritional status of the animal, in its response to stresses
(inflammation, heavy metal toxicity), and in embryonic, fetal and neonatal development.
The complementary DNAs and genes that encode the metallothioneins have been cloned and
analyzed from a wide variety of eukaryotes. Striking features of the metallothioneins
include: their high degree of amino acid sequence similarity (including conservation in
the placement of cysteine residues in the molecule reflecting their
function in metal binding); a conserved tripartite gene structure; and their
transcriptional induction by metal ions, as well as other hormonal and environmental
stimuli. The precise mechanisms and biochemical pathways by which cells transduce
environmental signals into transcriptional induction of the metallothionein genes are
beginning to be defined. Recent studies indicate that metal effects are exerted via
positive trans-acting factors induced to interact with cis-acting DNA sequences in the
promoter, in turn leading to transcriptional induction. However, the metallothionein gene
promoter is structurally complex, and contains binding sites for a variety of nuclear
proteins that likely regulate basal as well as induced levels of expression of these
genes. Recent studies also suggest the possible involvement of post-transcriptional
processes in the regulation of metallothionein levels in the cell. Furthermore, evidence
of striking differences in the levels of metallothionein gene expression among various
cell types in vivo have recently been documented. Although several detailed reviews of the
metallothioneins have been published recently, this review will focus, in large part, on
the molecular biology of the metallothioneins, with particular emphasis on recent advances
in our understanding of the mechanisms regulating expression of these interesting and
important genes. Given the large volume of literature on the metallothioneins and the
space limitations of this review, it is impossible to comprehensively cite the studies of
each of my colleagues who have contributed so much to this field. Instead the reader is
often directed to reviews of this subject for much of the earlier literature, and emphasis
is placed on more current publications in this field.
- Language of Publication
- English
- Unique Identifier
- 91156807
- MeSH Heading (Major)
- Gene Expression Regulation|*; Metallothionein|CH/*GE
- MeSH Heading
- Amino Acid Sequence; Animal; Human; Molecular Sequence Data; Support, Non-U.S. Gov't;
Support, U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0306-0632
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 9038-94-2 (Metallothionein)
Record 131 from database: MEDLINE
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- Title
- Bioactive organosulfur phytochemicals in Brassica oleracea vegetables--a review.
- Author
- Stoewsand GS
- Address
- Department of Food Science and Technology, New York State Agricultural Experiment
Station, Cornell University, Geneva 14456, USA.
- Source
- Food Chem Toxicol, 1995 Jun, 33:6, 537-43
- Abstract
- Sulfur-containing phytochemicals of two different kinds are present in all Brassica
oleracea (Cruciferae) vegetables (cabbage, broccoli, etc.). They are glucosinolates
(previously called thioglucosides) and S-methyl cysteine sulfoxide. These
compounds, which are derived in plant tissue by amino acid biosynthesis, show quite
different toxicological effects and appear to possess anticarcinogenic properties.
Glucosinolates have been extensively studied since the mid-nineteenth century. They are
present in plant foods besides Brassica vegetables with especially high levels in a number
of seed meals fed to livestock. About 100 different kinds of glucosinolates are known to
exist in the plant kingdom, but only about 10 are present in Brassica. The first toxic
effects of isothiocyanates and other hydrolytic products from glucosinolates that were
identified were goitre and a general inhibition of iodine uptake by the thyroid. Numerous
studies have indicated that the hydrolytic products of at least three glucosinolates,
4-methyl-sulfinylbutyl (glucoraphanin), 2-phenylethyl (gluconasturtiin) and
3-indolylmethyl (glucobrassicin), have anticarcinogenic activity. Indole-3-carbinol, a
metabolite of glucobrassicin, has shown inhibitory effects in studies of human breast and
ovarian cancers. Kale poisoning, or a severe haemolytic anaemia, was discovered in cattle
in Europe in the 1930s, but its link with the hydrolytic product of S-methyl cysteine
sulfoxide was only shown about 35 years later. S-methyl cysteine
sulfoxide and its metabolite methyl methane thiosulfinate were shown to inhibit
chemically-induced genotoxicity in mice. Thus, the cancer chemopreventive effects of
Brassica vegetables that have been shown in human and animal studies may be due to the
presence of both types of sulfur-containing phytochemicals (i.e. certain glucosinolates
and S-methyl cysteine sulfoxide).
- Language of Publication
- English
- Unique Identifier
- 95317721
- MeSH Heading (Major)
- Brassica|*CH; Cysteine|*AA/AN/PD/TO; Glucosinolates|*AN/PD/TO
- MeSH Heading
- Animal; Anticarcinogenic Agents|AN; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0278-6915
- Country of Publication
- ENGLAND
Record 132 from database: MEDLINE
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- Title
- Use of N-acetylcysteine in clinical toxicology.
- Author
- Flanagan RJ; Meredith TJ
- Address
- Poisons Unit, Guy's Hospital, London, U.K.
- Source
- Am J Med, 1991 Sep 30, 91:3C, 131S-139S
- Abstract
- The major use of N-acetylcysteine in clinical toxicology is in the treatment of
acetaminophen (paracetamol) overdosage. The hepatorenal toxicity of acetaminophen is
mediated by a reactive metabolite normally detoxified by reduced glutathione. If
glutathione is depleted, covalent binding to macromolecules and/or oxidation of thiol
enzymes can lead to cell death. Oral or intravenous N-acetylcysteine or oral
D,L-methionine mitigates acetaminophen-induced hepatorenal damage if given within 10
hours, but becomes less effective thereafter. In vivo, N-acetylcysteine forms L-cysteine,
cystine, L-methionine, glutathione, and mixed disulfides; L-methionine also forms cysteine,
thus giving rise to glutathione and other products. Oral therapy with N-acetylcysteine or
methionine for acetaminophen poisoning is contraindicated in the presence of coma or
vomiting, or if activated charcoal has been given by mouth. Nausea, vomiting, and diarrhea
may also occur as a result of oral N-acetylcysteine administration. Anaphylactoid
reactions including angioedema, bronchospasm, flushing, hypotension, nausea/vomiting,
rash, tachycardia, and respiratory distress may occur 15-60 minutes into N-acetylcysteine
infusion (20 hours intravenous regimen) in up to 10% of patients. Following accidental
intravenous overdosage, the adverse reactions of N-acetylcysteine are similar but more
severe; fatalities have occurred. A reduction in the loading dose of N-acetylcysteine may
reduce the risk of adverse reactions while maintaining efficacy. Administration of
N-acetylcysteine for a longer period might provide enhanced protection for patients in
whom acetaminophen absorption or elimination is delayed. N-acetylcysteine may also have a
role in the treatment of toxicity from carbon tetrachloride, chloroform,
1,2-dichloropropane, and other compounds. The possible use of N-acetylcysteine and other
agents in the prevention of the neuropsychiatric sequelae of acute carbon monoxide
poisoning is an important area for future research.
- Language of Publication
- English
- Unique Identifier
- 92026222
- MeSH Heading (Major)
- Acetaminophen|ME/*PO; Acetylcysteine|*CT/ME/PK
- MeSH Heading
- Animal; Human; Poisoning|DT; Toxicology
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0002-9343
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 103-90-2 (Acetaminophen); 616-91-1 (Acetylcysteine)
Record 133 from database: MEDLINE
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- Title
- Glutathione-dependent bioactivation of xenobiotics.
- Author
- Dekant W; Vamvakas S
- Address
- Institut für Toxikologie und Pharmakologie, Universität Würzburg, Germany.
- Source
- Xenobiotica, 1993 Aug, 23:8, 873-87
- Abstract
- Glutathione conjugation has been identified as an important detoxication reaction.
However, in recent years several glutathione-dependent bioactivation reactions have been
identified. Current knowledge on the mechanisms and the possible biological importance of
these reactions are discussed. 1. Dichloromethane is metabolized by glutathione
conjugation to formaldehyde via S-(chloromethyl)glutathione. Both compounds are reactive
intermediates and may be responsible for the dichloromethane-induced tumorigenesis in
sensitive species. 2. Vicinal dihaloalkanes are transformed by glutathione
S-transferase-catalyzed reactions to mutagenic and nephrotoxic S-(2-haloethyl)glutathione
S-conjugates. Electrophilic episulphonium ions are the ultimate reactive intermediates
formed. 3. Several polychlorinated alkenes are bioactivated in a complex,
glutathione-dependent pathway. The first step is hepatic glutathione S-conjugate formation
followed by cleavage to the corresponding cysteine S-conjugates, and,
after translocation to the kidney, metabolism by renal cysteine conjugate
beta-lyase. Beta-Lyase-dependent metabolism of halovinyl cysteine
S-conjugates yields electrophilic thioketenes, whose covalent binding to cellular
macromolecules is responsible for the observed toxicity of the parent compounds. 4.
Finally, hepatic glutathione conjugate formation with hydroquinones and aminophenols
yields conjugates that are directed to gamma-glutamyltransferase-rich tissues, such as the
kidney, where they undergo alkylation or redox cycling reactions, or both, that cause
organ-selective damage.
- Language of Publication
- English
- Unique Identifier
- 94112861
- MeSH Heading (Major)
- Glutathione|BI/*PH; Xenobiotics|*PK
- MeSH Heading
- Amino Acid Sequence; Animal; Human; Metabolic Detoxication, Drug|PH; Molecular Sequence
Data; Molecular Structure
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0049-8254
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 0 (Xenobiotics); 70-18-8 (Glutathione)
Record 134 from database: MEDLINE
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- Title
- Management of early inflammatory arthritis. Genetic factors predicting persistent
disease: the role of defective enzyme systems.
- Author
- Waring RH; Emery P
- Address
-
- Source
- Baillieres Clin Rheumatol, 1992 Jun, 6:2, 337-50
- Abstract
- In this chapter, we investigate the use of non-toxic 'probe drugs' to give information
about basic biochemical pathways. We have examined the hypothesis that a major factor in
RA is defective metabolism of sulphur-containing compounds. At least two pathways have
been shown to be abnormal in RA. Generally, patients have reduced capacity to metabolize
and detoxify thiol compounds by methylation, and have increased levels of plasma cysteine.
They also have a lower capacity for S-oxidation of cysteine and its
derivatives, with reduced amounts of plasma sulphate. The raised cysteine
resulting from less effective metabolism may lead to reduced clearance of immune complexes
and a raised inflammatory response in RA patients. Lower plasma sulphate, however, leads
to defective tissue synthesis, and makes adequate repair of damaged joints less feasible.
The co-existence of defects in these two interacting endogenous pathways serves to
perpetuate the disease process, leading to chronic inflammation and tissue destruction.
These enzyme defects have been shown to be predictive of persistent disease.
- Language of Publication
- English
- Unique Identifier
- 92405185
- MeSH Heading (Major)
- Arthritis, Rheumatoid|EN/*GE/ME
- MeSH Heading
- Acetaminophen|ME; Carbocysteine|ME; Cysteine|ME; Forecasting; Human;
Metabolic Detoxication, Drug; Methylation; Methyltransferases|ME; Oxidation-Reduction;
Sulfates|ME
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0950-3579
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- EC 2.1.1. (Methyltransferases); EC 2.1.1.9 (thiol S-methyltransferase); 0 (Sulfates);
103-90-2 (Acetaminophen); 2387-59-9 (Carbocysteine); 4371-52-2 (Cysteine)
Record 135 from database: MEDLINE
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- Title
- Glutathione metabolism and its role in hepatotoxicity.
- Author
- DeLeve LD; Kaplowitz N
- Address
- University of Southern California, Division of Gastrointestinal and Liver Diseases, Los
Angeles.
- Source
- Pharmacol Ther, 1991 Dec, 52:3, 287-305
- Abstract
- Glutathione (GSH) fulfills several essential functions: Detoxification of free radicals
and toxic oxygen radicals, thiol-disulfide exchange and storage and transfer of cysteine.
GSH is present in all mammalian cells, but may be especially important for organs with
intense exposure to exogenous toxins such as the liver, kidney, lung and intestine. Within
the cell mitochondrial GSH is the main defense against physiological oxidant stress
generated by cellular respiration and may be a critical target for toxic oxygen and
electrophilic metabolites. Glutathione homeostasis is a highly complex process, which is
predominantly regulated by the liver, lung and kidney.
- Language of Publication
- English
- Unique Identifier
- 92319812
- MeSH Heading (Major)
- Glutathione|*/BI/ME/PH; Glutathione Transferases|*ME; Liver|*ME/PH
- MeSH Heading
- Animal; Cysteine|ME; Homeostasis; Human; Oxidation-Reduction; Support,
U.S. Gov't, Non-P.H.S.; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0163-7258
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- EC 2.5.1.18 (Glutathione Transferases); 4371-52-2 (Cysteine); 70-18-8
(Glutathione)
Record 136 from database: MEDLINE
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- Title
- Multiple roles of glutathione in the central nervous system.
- Author
- Cooper AJ; Kristal BS
- Address
- Department of Biochemistry, Cornell University Medical College, New York, NY 10021, USA.
- Source
- Biol Chem, 1997 Aug, 378:8, 793-802
- Abstract
- Glutathione is a storage form of cysteine and protects against reactive
oxygen species and potentially toxic xenobiotics in the central nervous system. Marked
reductions in intracellular or intramitochondrial glutathione are associated with cell
death. Enzymes involved in glutathione metabolism are very active in the choroid plexus,
and astrocytes maintain a high concentration of glutathione. Astrocytes probably play an
important role in regulating cerebral sulfur/glutathione metabolism and in protecting the
brain against noxious chemicals. Oxidative stress contributes to age-related
neurodegenerative diseases. Patients with inborn errors of glutathione metabolism often
exhibit progressive neurological problems. Therefore, increasing brain glutathione levels
may have therapeutic benefits.
- Language of Publication
- English
- Unique Identifier
- 98020804
- MeSH Heading (Major)
- Central Nervous System|CY/*PH; Glutathione|BI/ME/*PH
- MeSH Heading
- Animal; Astrocytes|ME/PH; Brain Chemistry|PH; Glutathione Disulfide|ME; Human; Support,
Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 1431-6730
- Country of Publication
- GERMANY
Record 137 from database: MEDLINE
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- Title
- Toxicity and carcinogenicity of potassium bromate--a new renal carcinogen.
- Author
- Kurokawa Y; Maekawa A; Takahashi M; Hayashi Y
- Address
- Division of Toxicology, National Institute of Hygienic Sciences, Tokyo, Japan.
- Source
- Environ Health Perspect, 1990 Jul, 87:, 309-35
- Abstract
- Potassium bromate (KBrO3) is an oxidizing agent that has been used as a food additive,
mainly in the bread-making process. Although adverse effects are not evident in animals
fed bread-based diets made from flour treated with KBrO3, the agent is carcinogenic in
rats and nephrotoxic in both man and experimental animals when given orally. It has been
demonstrated that KBrO3 induces renal cell tumors, mesotheliomas of the peritoneum, and
follicular cell tumors of the thyroid. In addition, experiments aimed at elucidating the
mode of carcinogenic action have revealed that KBrO3 is a complete carcinogen, possessing
both initiating and promoting activities for rat renal tumorigenesis. However, the
potential seems to be weak in mice and hamsters. In contrast to its weak mutagenic
activity in microbial assays, KBrO3 showed relatively strong potential inducing chromosome
aberrations both in vitro and in vivo. Glutathione and cysteine degrade
KBrO3 in vitro; in turn, the KBrO3 has inhibitory effects on inducing lipid peroxidation
in the rat kidney. Active oxygen radicals generated from KBrO3 were implicated in its
toxic and carcinogenic effects, especially because KBrO3 produced 8-hydroxydeoxyguanosine
in the rat kidney. A wide range of data from applications of various analytical methods
are now available for risk assessment purposes.
- Language of Publication
- English
- Unique Identifier
- 91099248
- MeSH Heading (Major)
- Bread|*/AN; Bromates|AE/PK/PO/*TO; Carcinogens|PK/*TO; Carcinoma, Renal Cell|*CI; Food
Additives|AE/*TO; Hair Preparations|*PO; Kidney Neoplasms|*CI
- MeSH Heading
- Adenocarcinoma|CI; Administration, Oral; Animal; Bromides|AN/TO; Carcinogenicity Tests;
Chromosome Aberrations; Cocarcinogenesis; Comparative Study; Cysteine|ME;
Dose-Response Relationship, Drug; Fish Products; Food Handling; Glutathione|ME; Great
Britain; Hamsters; Hearing Loss, Partial|CI; Human; Japan|EP; Kidney Diseases|CI; Maximum
Permissible Exposure Level; Mesocricetus; Mesothelioma|CI; Mice; Mutagenicity Tests;
Occupational Diseases|CI/EP; Peritoneal Neoplasms|CI; Potassium|AN/TO; Rats; Rats, Inbred
F344|RATS INBRED F 344; Species Specificity; Support, Non-U.S. Gov't; Thyroid
Neoplasms|CI; United States|EP
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0091-6765
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Bromates); 0 (Bromides); 0 (Carcinogens); 0 (Food Additives); 0 (Hair Preparations);
4371-52-2 (Cysteine); 70-18-8 (Glutathione); 7440-09-7 (Potassium);
7758-01-2 (potassium bromate); 7758-02-3 (potassium bromide)
Record 138 from database: MEDLINE
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- Title
- Involvement of metallothionein and copper in cell proliferation.
- Author
- W
ostowski T
- Address
- Institute of Biology, Warsaw University, Bia
ystok, Poland.
- Source
- Biometals, 1993 Summer, 6:2, 71-6
- Abstract
- Metallothionein is a low-molecular weight, cysteine-rich, metal-binding
protein which has been implicated in the detoxification of toxic metals (cadmium,
mercury), metabolism of zinc and copper, as well as in the scavenging of free radicals.
Recent evidence suggests that the protein may also be involved in cell proliferation.
Based on the experiments carried out so far, it is assumed that the fundamental role of
metallothionein in cell proliferation may be to detoxify and/or transfer copper ions from
the cytoplasm to the nucleus at the G1/S phase, which in turn participate in some way in
nuclear DNA synthesis.
- Language of Publication
- English
- Unique Identifier
- 93364161
- MeSH Heading (Major)
- Cell Division|*; Copper|*ME; Metallothionein|*ME
- MeSH Heading
- Amino Acid Sequence; Animal; Cell Cycle; Conserved Sequence; Evolution; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0966-0844
- Country of Publication
- ENGLAND
- CAS Registry/EC Number
- 7440-50-8 (Copper); 9038-94-2 (Metallothionein)
Record 139 from database: MEDLINE
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- Title
- N-acetyl-S-(2-hydroxyethyl)-L-cysteine as a potential tool in
biological monitoring studies? A critical evaluation of possibilities and limitations.
- Author
- Vermeulen NP; de Jong J; van Bergen EJ; van Welie RT
- Address
- Department of Pharmacochemistry, Free University, Amsterdam, The Netherlands.
- Source
- Arch Toxicol, 1989, 63:3, 173-84
- Abstract
- In mammalian species, including man, N-acetyl-S-(2-hydroxyethyl)-L-cysteine
(2-HEMA) is a common urinary metabolite of a large number of structurally different
xenobiotic chemicals. It is a common urinary end product of glutathione pathway metabolism
of a variety of chemicals possessing electrophilic properties and, in most cases, also a
genotoxic potential. Five different chemically reactive intermediates, with different
electrophilic properties, may be involved in the formation of 2-HEMA. An inventory of
chemicals known to lead to the formation of 2-HEMA, or based on their chemical structure
expected to do so, is presented. Furthermore, an attempt is made to evaluate the
possibilities and limitations in terms of the potential use of urinary 2-HEMA as a tool in
biomonitoring studies. Two other related, sulfur-containing urinary metabolites, i.e.
N-acetyl-(S-carboxymethyl)-L-cysteine and thio-diacetic acid, are
proposed as possible alternatives to urinary 2-HEMA. It is suggested that 2-HEMA might be
seen as a potentially useful and sensitive signal parameter for the assessment of exposure
of animals and man to a variety of electrophilic and therefore potentially toxic
xenobiotic chemicals.
- Language of Publication
- English
- Unique Identifier
- 89350446
- MeSH Heading (Major)
- Acetylcysteine|*AA/UR; Environmental Monitoring|*
- MeSH Heading
- Animal; Biological Markers|UR; Environmental Pollution; Human
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0340-5761
- Country of Publication
- GERMANY, WEST
- CAS Registry/EC Number
- 0 (Biological Markers); 19179-72-7 (N-acetyl-S-(2-hydroxyethyl)cysteine); 616-91-1
(Acetylcysteine)
Record 140 from database: MEDLINE
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- Title
- Acrylamide and polyacrylamide: a review of production, use, environmental fate and
neurotoxicity.
- Author
- Smith EA; Oehme FW
- Address
- Comparative Toxicology Laboratories, College of Veterinary Medicine, Kansas State
University, Manhattan 66506-5606.
- Source
- Rev Environ Health, 1991 Oct-Dec, 9:4, 215-28
- Abstract
- Acrylamide is a highly water soluble vinyl monomer formed from the hydration of
acrylonitrile. The major commercial use of acrylamide is the formation of polymers. In the
environment acrylamide has a high mobility in soil, may travel great distances in
ground-water, is biodegradable, and is not absorbed by sediments or affected by water
treatment. It is absorbed by all routes of animal exposure. The main metabolite is
N-acetyl-S-(3-amino-3-oxypropyl)-cysteine and is excreted predominantly in the urine.
Acrylamide produces an ascending central/peripheral axonopathy in man and animals. The
major histological findings are swelling of axons and/or decrease in number of large
diameter axons. Acrylamide axonopathy is reversible with time, but full recovery depends
upon the severity of the intoxication. All reported cases of acrylamide toxicity have been
attributed to handling the monomer. Polyacrylamide is non-toxic. Specific clinical
features of acrylamide intoxication are more conclusive than electrophysiological,
histological or biochemical laboratory tests for diagnosis. Acrylamide can be detected by
titration, colorimetry, high performance chromatography, gas chromatography and
polarography in air, water, biological fluids, tissues and polyacrylamides. Present
research on the effects of acrylamide focuses on developmental and reproductive effects,
genotoxicity and carcinogenicity.
- Language of Publication
- English
- Unique Identifier
- 93087827
- MeSH Heading (Major)
- Acrylamides|CH/PK/*PO; Occupational Exposure|*AE; Peripheral Nervous System
Diseases|*CI/TH
- MeSH Heading
- Acrylic Resins|CH; Animal; Cats; Guinea Pigs; Human; Mice; Rats
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0048-7554
- Country of Publication
- ISRAEL
- CAS Registry/EC Number
- 0 (Acrylamides); 0 (Acrylic Resins); 9003-05-8 (polyacrylamide)
Record 141 from database: MEDLINE
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- Title
- Phenotypic variation in xenobiotic metabolism and adverse environmental response: focus
on sulfur-dependent detoxification pathways.
- Author
- McFadden SA
- Address
- Independent Research Advocates, Dallas, TX 75206, USA.
- Source
- Toxicology, 1996 Jul, 111:1-3, 43-65
- Abstract
- Proper bodily response to environmental toxicants presumably requires proper function of
the xenobiotic (foreign chemical) detoxification pathways. Links between phenotypic
variations in xenobiotic metabolism and adverse environmental response have long been
sought. Metabolism of the drug S-carboxymethyl-L-cysteine (SCMC) is
polymorphous in the population, having a bimodal distribution of metabolites, 2.5% of the
general population are thought to be nonmetabolizers. The researchers developing this data
feel this implies a polymorphism in sulfoxidation of the amino acid cysteine
to sulfate. While this interpretation is somewhat controversial, these metabolic
differences reflected may have significant effects. Additionally, a significant number of
individuals with environmental intolerance or chronic disease have impaired sulfation of
phenolic xenobiotics. This impairment is demonstrated with the probe drug acetaminophen
and is presumably due to starvation of the sulfotransferases for sulfate substrate.
Reduced metabolism of SCMC has been found with increased frequency in individuals with
several degenerative neurological and immunological conditions and drug intolerances,
including Alzheimer's disease, Parkinson's disease, motor neuron disease, rheumatoid
arthritis, and delayed food sensitivity. Impaired sulfation has been found in many of
these conditions, and preliminary data suggests that it may be important in multiple
chemical sensitivities and diet responsive autism. In addition, impaired sulfation may be
relevant to intolerance of phenol, tyramine, and phenylic food constituents, and it may be
a factor in the success of the Feingold diet. These studies indicate the need for the
development of genetic and functional tests of xenobiotic metabolism as tools for further
research in epidemiology and risk assessment.
- Language of Publication
- English
- Unique Identifier
- 96319826
- MeSH Heading (Major)
- Carbocysteine|*AA/PK; Environmental Pollutants|AE/*PK; Sulfur|*ME; Xenobiotics|AE/*PK
- MeSH Heading
- Human; Metabolic Detoxication, Drug; Multiple Chemical Sensitivity|ET/GE/ME; Phenotype;
Variation (Genetics)
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0300-483X
- Country of Publication
- IRELAND
Record 142 from database: MEDLINE
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- Title
- Oxygen free radicals and myocardial damage: protective role of thiol-containing agents.
- Author
- Ferrari R; Ceconi C; Curello S; Cargnoni A; Alfieri O; Pardini A; Marzollo P; Visioli O
- Address
- Cattedra di Cardiologia, Università degli Studi di Brescia, Italy.
- Source
- Am J Med, 1991 Sep 30, 91:3C, 95S-105S
- Abstract
- It has been suggested that the sudden presence of oxygen during reperfusion after a
period of ischemia may be toxic for the myocardial cell. The oxygen molecule is capable of
producing reactions in the cell, forming highly reactive free radicals, and inducing lipid
peroxidation of membranes, altering their integrity and increasing their fluidity and
permeability. The ischemic and reperfused cardiac cell is the prime candidate for this
reaction sequence and may explain the molecular mechanism underlying the pathologic events
related to membrane dysfunction and calcium homeostasis. However, the myocardium has a
series of defense mechanisms including the enzymes superoxide dismutase (SOD), catalase,
and glutathione peroxidase plus other endogenous antioxidants such as vitamin E, ascorbic
acid, and cysteine to protect the cell against the cytotoxic oxygen
metabolites. The prerequisite for oxygen free radical involvement in ischemia and
reperfusion damage is that ischemia alters the defense mechanisms against oxygen toxicity.
It is known that ischemia may impair mitochondrial SOD and, with reperfusion, oxidative
stress may occur as shown by tissue accumulation and release of oxidized glutathione. This
tripeptide molecule in the cofactor of glutathione peroxidase, the enzyme that removes
hydrogen and lipid peroxides. Its formation and subsequent release is a reliable index of
oxidative damage. In our study, we investigated the effects of N-acetylcysteine on
oxidative damage in the isolated rabbit heart. N-acetylcysteine increases, in a
dose-dependent manner (from 10(-7) to 10(-5) M), the myocardial glutathione content and
provides an important degree of protection against ischemia and reperfusion. Oxidative
stress does not occur, mitochondrial function is maintained, enzyme release is reduced,
and contractile recovery is increased. Similarly, we administered N-acetylcysteine in the
pulmonary artery of coronary artery disease patients undergoing coronary bypass grafting
(150 mg/kg in 1 hour followed by 150 mg/kg in 4 hours). The degree of oxidative stress on
reperfusion was reduced and recovery of cardiac function improved. In this article, we
review the cardioprotective role of thiol-containing agents.
- Language of Publication
- English
- Unique Identifier
- 92026237
- MeSH Heading (Major)
- Antioxidants|ME/*TU; Myocardial Reperfusion Injury|*PC; Myocardium|*ME; Oxidants|*ME;
Sulfhydryl Compounds|*TU
- MeSH Heading
- Animal; Coronary Disease|ME; Free Radicals|ME; Human; Models, Biological;
Neutrophils|DE/ME; Oxygen|AI; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0002-9343
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Antioxidants); 0 (Free Radicals); 0 (Oxidants); 0 (Sulfhydryl Compounds); 7782-44-7
(Oxygen)
Record 143 from database: MEDLINE
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- Title
- N-acetylcysteine in experimental and clinical acute lung injury.
- Author
- Bernard GR
- Address
- Department of Medicine, Vanderbilt University, Nashville, Tennessee 37232.
- Source
- Am J Med, 1991 Sep 30, 91:3C, 54S-59S
- Abstract
- Clinically, lung injury is characterized by one or more of the following: altered gas
exchange, dyspnea, decreased static compliance, and nonhydrostatic pulmonary edema.
Although many antioxidants have been investigated in in vitro systems and in animal
models, only some are at the developmental stage, or safe for clinical trials.
Considerable evidence has recently accumulated supporting the hypothesis that leukocyte
activation involves release of large quantities of highly reactive oxygen radicals, and
hydrogen peroxide is partially responsible for diffuse microvascular and tissue injury in
septic patients. Granulocyte depletion in animal models reduces the degree of fall in
dynamic lung compliance and the increase in airflow resistance, lymph flow, and hypoxemia
secondary to endotoxin administration. We hypothesized that the partial benefit derived
from granulocyte depletion was due to the effective removal of a major source of oxygen
radicals. Among the list of free radical scavengers, N-acetylcysteine stands out, because
of its established usefulness in at least one human disease thought to be secondary to
free radical organ damage (acetaminophen or paracetamol overdose). It is an extremely safe
agent with a wide toxic-therapeutic window. An increasing number of animal studies
indicate efficacy for this agent in the prevention and therapy of lung injury involving
toxic oxygen species. We developed a randomized, double-blind protocol for the study of
intravenous N-acetylcysteine in patients with established adult respiratory distress
syndrome (ADRS). Results of this trial are preliminary. Nevertheless, they indicate that
plasma and red cell glutathione levels are decreased in ADRS patients, and that
N-acetylcysteine increases plasma cysteine as well as plasma and red cell
glutathione. There are also indications that cardiopulmonary physiology is favorably
affected by such therapy including improvements in chest radiograph edema scores,
pulmonary vascular resistance, static compliance, oxygen delivery, and oxygen consumption.
- Language of Publication
- English
- Unique Identifier
- 92026230
- MeSH Heading (Major)
- Acetylcysteine|*TU; Free Radical Scavengers|*; Lung Diseases|*DT/ME; Respiratory
Distress Syndrome, Adult|*DT
- MeSH Heading
- Animal; Clinical Trials; Endotoxins|PD; Glutathione|ME; Granulocytes|DE/ME; Human;
Models, Biological; Support, Non-U.S. Gov't; Support, U.S. Gov't, P.H.S.
- Publication Type
- CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED CONTROLLED TRIAL; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0002-9343
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Endotoxins); 0 (Free Radical Scavengers); 616-91-1 (Acetylcysteine); 70-18-8
(Glutathione)
Record 144 from database: MEDLINE
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- Title
- Pharmacological actions of melatonin in oxygen radical pathophysiology.
- Author
- Reiter R; Tang L; Garcia JJ; Muñoz Hoyos A
- Address
- Department of Cellular and Structural Biology, University of Texas Health Science
Center, San Antonio 78284-7762, USA.
- Source
- Life Sci, 1997, 60:25, 2255-71
- Abstract
- Melatonin, the chief secretory product of the pineal gland, was recently found to be a
free radical scavenger and antioxidant. This review briefly summarizes the published
reports supporting this conclusion. Melatonin is believed to work via electron donation to
directly detoxify free radicals such as the highly toxic hydroxyl radical. Additionally,
in both in vitro and in vivo experiments, melatonin has been found to protect cells,
tissues and organs against oxidative damage induced by a variety of free radical
generating agents and processes, e.g., the carcinogen safrole, lipopolysaccharide, kainic
acid, Fenton reagents, potassium cyanide, L-cysteine, excessive exercise,
glutathione depletion, carbon tetrachloride, ischemia-reperfusion, MPTP, amyloid beta
(25-35 amino acid residue) protein, and ionizing radiation. Melatonin as an antioxidant is
effective in protecting nuclear DNA, membrane lipids and possibly cytosolic proteins from
oxidative damage. Also, melatonin has been reported to alter the activities of enzymes
which improve the total antioxidative defense capacity of the organism, i.e., superoxide
dimutase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate
dehydrogenase, and nitric oxide synthase. Most studies have used pharmacological
concentrations or doses of melatonin to protect against free radical damage; in a few
studies physiological levels of the indole have been shown to be beneficial against
oxidative stress. Melatonin's function as a free radical scavenger and antioxidant is
likely assisted by the ease with which it crosses morphophysiological barriers, e.g., the
blood-brain barrier, and enters cells and subcellular compartments. Whether the quantity
of melatonin produced in vertebrate species is sufficient to significantly influence the
total antioxidative defense capacity of the organism remains unknown, but its
pharmacological benefits seem assured considering the low toxicity of the molecule.
- Language of Publication
- English
- Unique Identifier
- 97338010
- MeSH Heading (Major)
- Antioxidants|*PD; Free Radical Scavengers|*PD; Melatonin|*PD/PH; Reactive Oxygen
Species|*ME
- MeSH Heading
- Animal; Human; Lipid Peroxidation|DE
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0024-3205
- Country of Publication
- ENGLAND
Record 145 from database: MEDLINE
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- Title
- meso-2,3-Dimercaptosuccinic acid: chemical, pharmacological and toxicological properties
of an orally effective metal chelating agent.
- Author
- Aposhian HV; Aposhian MM
- Address
- Department of Molecular and Cellular Biology, University of Arizona, Tucson 85721.
- Source
- Annu Rev Pharmacol Toxicol, 1990, 30:, 279-306
- Abstract
- The primary purpose of this article is to summarize the recent investigations dealing
with the pharmacology and toxicology of meso-2,3-dimercaptosuccinic acid, an orally
effective chelating agent. The need for a better chelating agent for treating young
children and pregnant women with lead intoxication has been apparent for some time.
Preclinical and clinical evidence now indicate that meso-2,3-dimercaptosuccinic acid, an
Orphan Drug, shows the most promise for being effective in this regard. It has an
extracellular distribution that may be responsible for its low toxicity compared to other
dithiols. No attempt has been made to compare it in a rigorous and thorough manner with
other chelating agents. That has not been the purpose of this review. The advantages of
meso-DMSA, however, compared to CaNa2EDTA for the treatment of lead intoxication, have
been outlined. Significant advances have been made recently in elucidating the structures
of the metal chelates of DMSA. There is a striking difference between the structures of
the lead chelate of meso-DMSA and those of racemic-DMSA. The former chelates by
coordination of one sulfur and one oxygen atom with Pb. The latter can form chelates via
the two sulfur atoms or via one oxygen and one sulfur atom. Solubility of the lead
chelates depends on the ionization of the noncoordinated thiol and carboxylic acid groups.
Bimane derivatization, HPLC, and fluorescence, as well as gas chromatography can be used
for analysis of DMSA in biological fluids. The acid dissociation constants for meso- and
racemic-DMSA have been summarized from the literature as have the formation constants of
some of the DMSA chelates. DMSA is biotransformed to a mixed disulfide in humans. By 14 hr
after DMSA administration (10 mg/kg), only 2.5% of the administered DMSA is excreted in
the urine as unaltered DMSA and 18.1% of the dose is found in the urine as altered forms
of DMSA. Most altered DMSA in the urine is in the form of a mixed disulfide. It consists
of DMSA in disulfide linkages with two molecules of L-cysteine. One
molecule of cysteine is attached to each of the sulfur atoms of DMSA. The
remaining 10% of the altered DMSA was in the form of cyclic disulfides of DMSA. So far,
the mixed disulfide has been found in human but not in rabbit, mouse, or rat urine.
Apparently there are species differences in how organisms metabolize meso-DMSA.(ABSTRACT
TRUNCATED AT 400 WORDS)
- Language of Publication
- English
- Unique Identifier
- 90262138
- MeSH Heading (Major)
- Chelating Agents|*; Succimer|AN/*PD/TO; Sulfhydryl Compounds|*PD
- MeSH Heading
- Animal; Human; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0362-1642
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Chelating Agents); 0 (Sulfhydryl Compounds); 304-55-2 (Succimer)
Record 146 from database: MEDLINE
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- Title
- Alkylation of macromolecules for detecting mutagenic agents.
- Author
- Ehrenberg L; Osterman-Golkar S
- Address
-
- Source
- Teratog Carcinog Mutagen, 1980, 1:1, 105-27
- Abstract
- At present, experiments with laboratory organisms and epidemiological studies are the
major source of information about the genetic toxicology of environmental agents.
Laboratory systems are limited in value by difficulties in the interpretation of negative
results, in quantitation, and in extrapolation from experimental effects of chemicals to
specific levels of activity in man. Epidemiologic methods measure effects in man but are
weakened by long latency times, confounding environmental factors, imprecise endpoints,
and high background levels, which reduce sensitivity. Several methodological improvements
in genetic toxicity testing are needed, including increased resolving power, greater
relevance of observations to effects in man, techniques for evaluating interactions of
compounds in chemically complex systems, and improvements in quantitative risk assessment.
Because most genetically toxic agents ultimately react as electrophilic agents with
nucleophilic centers in cellular macromolecules, the quantitative analysis of the
resulting products may be a useful approach to the evaluation of the risks posed by
exposure to specific chemicals. The main nucleophilic centers in biological macromolecules
are thiol and thioether sulfurs, nitrogens in amino groups and rings, and oxygen atoms.
Using the laws of reaction kinetics of alkylation and the observed kinetics of induced
mutagenic effects, it is possible to relate the formation of alkylated products in
macromolecules to genetic toxicity. The alkylation of amino acids (eg, histidine and cysteine)
in hemoglobin can be measured with sufficient sensitivity and accuracy to use it as a
monitor of exposure to alkylating agents. By determining the degree of alkylation of a
specific center, it is possible to calculate the internal dose of an agent and, because
erythrocyte life-spans are relatively uniform, the incremental daily exposure of an
individual to an alkylating agent. Dosimetry can be equated with radiologic dose so that
exposure can be expressed in rad-equivalents and the effects of specific agents compared
quantitatively to biologically well-characterized doses of radiation.
- Language of Publication
- English
- Unique Identifier
- 82108247
- MeSH Heading (Major)
- Macromolecular Systems|*; Mutagenicity Tests|*MT
- MeSH Heading
- Alkylation; Animal; Carcinogens|PD; Chemistry; Dose-Response Relationship, Drug;
Hemoglobins|AN; Human; Kinetics; Neoplasms, Experimental|CI; Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0270-3211
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Carcinogens); 0 (Macromolecular Systems)
Record 147 from database: MEDLINE
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- Title
- Bleomycin pharmacology: mechanism of action and resistance, and clinical
pharmacokinetics.
- Author
- Dorr RT
- Address
- Department of Internal Medicine and Pharmacology, University of Arizona, College of
Medicine, Tucson.
- Source
- Semin Oncol, 1992 Apr, 19:2 Suppl 5, 3-8
- Abstract
- Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity.
The drug binds to guanosine-cytosine-rich portions of DNA via association of the
"S" tripeptide and by partial intercalation of the bithiazole rings. A group of
five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals
including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound
by the iron, can produce highly reactive free radicals and Fe(III). The free radicals
produce DNA single-strand breaks at 3'-4' bonds in deoxyribose. This yields free base
propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase.
In humans, bleomycin is rapidly eliminated primarily by renal excretion. This accounts for
approximately half of a dose. In patients with renal compromise or extensive prior
cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours. Thus,
dose adjustments are needed when creatinine clearance is less than or equal to 3N mL/min.
Finally, resistance to bleomycin in normal tissues can be correlated with the presence of
a bleomycin hydrolase enzyme, which is in the cysteine proteinase family.
The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and
cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the
unique sensitivity of these tissues to bleomycin toxicity. However, correlation of
hydrolase levels with tumor cell sensitivity has thus far been negative.
- Language of Publication
- English
- Unique Identifier
- 93030884
- MeSH Heading (Major)
- Bleomycin|AI/CH/*PD/PK
- MeSH Heading
- Glycoside Hydrolases|PD; Human; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0093-7754
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- EC 3.2.1. (Glycoside Hydrolases); EC 3.4.22.- (bleomycin hydrolase); 11056-06-7
(Bleomycin)
Record 148 from database: MEDLINE
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- Title
- Thiazolidine-4-carboxylic acid, a physiologic sulfhydryl antioxidant with potential
value in geriatric medicine.
- Author
- Weber HU; Fleming JF; Miquel J
- Address
-
- Source
- Arch Gerontol Geriatr, 1982 Dec, 1:4, 299-310
- Abstract
- Thiazolidine-4-carboxylic acid (TC) is a cyclic sulfur amino acid, a condensation
product of cysteine and formaldehyde. The chemistry, biological effects
and clinical use of TC are reviewed. Extensive animal experiments and studies on human
subjects carried out in Europe indicate that a combination of TC and folic acid,
'Folcysteine', has revitalizing effects on age-related biochemical variables of blood and
tissues. Further animal studies confirmed the anti-toxic effects of TC, particularly on
the liver. The evidence accumulated so far suggests that addition of TC to the diet slows
the aging process in mammals and prolongs their life span. On the other hand, findings
suggesting that TC caused reverse transformation of tumor cells into normal cells and was
effective against human cancers could not be confirmed in additional studies. TC has been
clinically used for about 20 yr, mainly in the treatment of liver diseases and related
gastrointestinal disturbances. Derivatives of TC with similar applications have been
developed. Djenkolic acid is a naturally occurring relative of TC which is abundant in
djenkol beans. The toxic effects of djenkolic acid and its possible conversion into TC are
discussed.
- Language of Publication
- English
- Unique Identifier
- 83307675
- MeSH Heading (Major)
- Antioxidants|ME/*TU; Thiazoles|ME/*TU
- MeSH Heading
- Aged; Animal; Chemistry; Cysteine|TU; Dogs; Drug Combinations|TU; Folic
Acid|TU; Gastrointestinal Diseases|DT; Human; Liver Diseases|DT; Longevity|DE; Mice; Rats
- Publication Type
- JOURNAL ARTICLE; REVIEW
- ISSN
- 0167-4943
- Country of Publication
- NETHERLANDS
- CAS Registry/EC Number
- 0 (Antioxidants); 0 (Drug Combinations); 0 (Thiazoles); 4371-52-2 (Cysteine);
444-27-9 (thiazolidine-4-carboxylic acid); 59-30-3 (Folic Acid); 8064-47-9 (folcysteine)
Record 149 from database: MEDLINE
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- Title
- Glutathione mercaptides as transport forms of metals.
- Author
- Ballatori N
- Address
- Department of Environmental Medicine, University of Rochester School of Medicine, New
York 14642.
- Source
- Adv Pharmacol, 1994, 27:, 271-98
- Abstract
- Among the many cellular functions of GSH, the roles of this tripeptide in metal
transport, storage, and metabolism have recently received considerable attention. Although
these roles had often been overlooked, they are critical for normal cellular metabolism
and for protection from xenobiotics. Indeed, a number of the protective and regulatory
functions of GSH are related to its ability to chelate reactive metals. GSH functions in
the mobilization and delivery of metals between ligands, in the transport of metals across
cell membranes, as a source of cysteine for metal binding, and as a
reductant or cofactor in redox reactions involving metals. However, the interaction
between GSH and metals can also produce or exacerbate cell injury. For example, GSH
appears to be involved in the renal accumulation and toxicity of a number of metals, and
in the carcinogenicity of chromium. Additional work is clearly needed to identify the
mechanisms involved, and to better define the roles of GSH in metal homeostasis.
- Language of Publication
- English
- Unique Identifier
- 94347639
- MeSH Heading (Major)
- Glutathione|*ME; Metals|*ME/TO; Sulfhydryl Compounds|*ME
- MeSH Heading
- Animal; Biological Transport; Human; Oxidation-Reduction; Support, U.S. Gov't, P.H.S.
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 1054-3589
- Country of Publication
- UNITED STATES
Record 150 from database: MEDLINE
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- Title
- Neuronal nitric oxide synthase, a modular enzyme formed by convergent evolution:
structure studies of a cysteine thiolate-liganded heme protein that
hydroxylates L-arginine to produce NO. as a cellular signal [published erratum appears in
FASEB J 1996 Jul;10(9):1107]
- Author
- Masters BS; McMillan K; Sheta EA; Nishimura JS; Roman LJ; Martasek P
- Address
- Department of Biochemistry, University of Texas Health Science Center at San Antonio
78284-7760, USA.
- Source
- FASEB J, 1996 Apr, 10:5, 552-8
- Abstract
- The nitric oxide synthases (NOS-I, neuronal, NOS-II, inducible, and NOS-III,
endothelial) are the most recent additions to the large number of heme proteins that
contain cysteine thiolate-liganded protoporphyrin IX heme prosthetic
groups. This group of oxygenating enzymes also includes one of the largest gene families,
that of the cytochromes P450, which have been demonstrated to be involved in the
hydroxylation of a variety of substrates, including endogenous compounds (steroids, fatty
acids, and prostaglandins) and exogenous compounds (therapeutic drugs, environmental
toxicants, and carcinogens). The substrates for cytochromes P450 are universally
hydrophobic while the physiological substrate for the nitric oxide synthases is the amino
acid L-arginine, a hydrophilic compound. This review will discuss the approaches being
used to study the structure and mechanism of neuronal nitric oxide synthase in the context
of its known prosthetic groups and regulation by Ca(2+)-calmodulin and/or
tetrahydrobiopterin (BH4).
- Language of Publication
- English
- Unique Identifier
- 96210310
- MeSH Heading (Major)
- Arginine|*ME; Isoenzymes|*CH/ME; Neurons|*EN; Nitric Oxide|*ME; Nitric-Oxide
Synthase|*CH/ME
- MeSH Heading
- Animal; Cysteine|CH; Free Radicals; Hemeproteins|CH; Human;
Hydroxylation
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0892-6638
- Country of Publication
- UNITED STATES
Record 151 from database: MEDLINE
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- Title
- Antioxidant activity and other mechanisms of thiols involved in chemoprevention of
mutation and cancer.
- Author
- De Flora S; Izzotti A; D'Agostini F; Cesarone CF
- Address
- Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
- Source
- Am J Med, 1991 Sep 30, 91:3C, 122S-130S
- Abstract
- Our studies provide evidence that thiols, such as N-acetyl-L-cysteine,
inhibit both spontaneous mutations and induced mutations in bacteria, prevent the in vivo
formation of carcinogen-DNA adducts, and suppress or delay the development of tumors or
preneoplastic lesions in rodents. N-Acetylcysteine and other thiols exert antioxidant
activity toward superoxide anion, hydrogen peroxide, and singlet oxygen, assessed in
bacterial genotoxicity models. In addition, several other mechanisms were shown to
contribute to their antimutagenic and anticarcinogenic activities, in the extracellular
environment and in nontarget or target cells. These mechanisms include blocking of
electrophilic metabolites and of direct-acting compounds, either of endogenous or
exogenous source, modulation of several xenobiotic-metabolizing pathways, and protection
of DNA-dependent nuclear enzymes. Chemoprevention of mutation and cancer by thiols is
particularly useful under conditions of reduced glutathione (GSH) depletion due to toxic
agents or to cancer-associated viral diseases, such as acquired immunodeficiency syndrome
(AIDS) or viral hepatitis B.
- Language of Publication
- English
- Unique Identifier
- 92026221
- MeSH Heading (Major)
- Anticarcinogenic Agents|*TU; Antimutagenic Agents|*TU; Neoplasms|*PC; Sulfhydryl
Compounds|*TU
- MeSH Heading
- Animal; DNA, Neoplasm|DE; Human; Mutagenicity Tests; Neoplasms, Experimental|PC;
Support, Non-U.S. Gov't
- Publication Type
- JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC
- ISSN
- 0002-9343
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 0 (Anticarcinogenic Agents); 0 (Antimutagenic Agents); 0 (DNA, Neoplasm); 0 (Sulfhydryl
Compounds)
Record 152 from database: MEDLINE
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- Title
- Liver enzyme abnormalities in Parkinson's disease.
- Author
- Tanner CM
- Address
- Clinical Center for Parkinson's Disease and Movement Disorders, San Jose, California.
- Source
- Geriatrics, 1991 Aug, 46 Suppl 1:, 60-3
- Abstract
- If toxicant exposure contributes to the cause of Parkinson's disease, poor function of
detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no
hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's
disease patients, several have been suggested to be dysfunctional in subgroups, such as
those with young age at disease onset. Specific enzymes implicated include several P450
enzymes, most notably P450 IID6, and cysteine dioxygenase. If hepatic
enzyme abnormalities contribute to the development of Parkinson's disease, molecular
genetic techniques may allow the development of screening tests to identify at-risk
subjects in order to intervene with protective therapies.
- Language of Publication
- English
- Unique Identifier
- 91372608
- MeSH Heading (Major)
- Liver|*EN; Parkinson Disease|GE/*ME
- MeSH Heading
- Cytochrome P-450|GE/PH; Debrisoquin|ME; Human; Phenotype;
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine|PD
- Publication Type
- DUPLICATE PUBLICATION; JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0016-867X
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 1131-64-2 (Debrisoquin); 28289-54-5 (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine);
9035-51-2 (Cytochrome P-450)
Record 153 from database: MEDLINE
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- Title
- Abnormal liver enzyme-mediated metabolism in Parkinson's disease: a second look.
- Author
- Tanner CM
- Address
- Clinical Center for Parkinson's Disease and Movement Disorders, San Jose, CA 95128.
- Source
- Neurology, 1991 May, 41:5 Suppl 2, 89-91; discussion 92
- Abstract
- If toxicant exposure contributes to the cause of Parkinson's disease, poor function of
detoxifying enzymes could increase vulnerability for Parkinson's disease. Although no
hepatic enzyme system has been shown universally to be dysfunctional in Parkinson's
disease patients, several have been suggested to be dysfunctional in subgroups, such as
those with young age at disease onset. Specific enzymes implicated include several P450
enzymes, most notably P450 IID6, and cysteine dioxygenase. If hepatic
enzyme abnormalities contribute to the development of Parkinson's disease, molecular
genetic techniques may allow the development of screening tests to identify at-risk
subjects in order to intervene with protective therapies.
- Language of Publication
- English
- Unique Identifier
- 91251963
- MeSH Heading (Major)
- Liver|*EN; Parkinson Disease|GE/*ME
- MeSH Heading
- Cytochrome P-450|GE/PH; Debrisoquin|ME; Human; Phenotype;
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine|PD
- Publication Type
- DUPLICATE PUBLICATION; JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL
- ISSN
- 0028-3878
- Country of Publication
- UNITED STATES
- CAS Registry/EC Number
- 1131-64-2 (Debrisoquin); 28289-54-5 (1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine);
9035-51-2 (Cytochrome P-450)
Record 154 from database: MEDLINE
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- Title
- The genetic origin of responses to drugs.
- Author
- Waring RH; Emery P
- Address
- School of Biochemistry, University of Birmingham, UK.
- Source
- Br Med Bull, 1995 Apr, 51:2, 449-61
- Abstract
- Individual variation in drug metabolism has been extensively investigated. Population
studies have shown that there is a wide range in metabolising ability for all
detoxific