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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.

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Table Of Definitions And Terms

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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

 

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Record 1 from database: MEDLINE

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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

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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

 

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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

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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

 

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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

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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

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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 11 from database: MEDLINE

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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

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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

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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

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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

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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

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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;

 

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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

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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

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Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0006-3002

Country of Publication

NETHERLANDS

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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

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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.

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Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, ACADEMIC

ISSN

0006-3525

Country of Publication

UNITED STATES

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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

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MeSH Heading (Major)

ras Proteins|*AI; Antineoplastic Agents|*PD; Enzyme Inhibitors|*PD; Transferases|*AI

MeSH Heading

Animal; Guanosine Triphosphate|ME; Human

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Publication Type

JOURNAL ARTICLE; REVIEW; REVIEW, TUTORIAL

ISSN

0167-6806

Country of Publication

NETHERLANDS

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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

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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

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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)

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