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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 pr