A Urinary Cysteine-Halothane Metabolite: Validation and Measurement in Children

Wark, H.; Earl, John; Chau, D. D.; Overton, John H.; Cheung, H. T. Andrew

doi:10.1093/bja/64.4.469

Cited by 18 publications

(4 citation statements)

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“…Bacterial mutagenicity studies lead to the generalization that S-(l-chloroalkenyl)-L-cysteine conjugates are mutagenic, but that S-(l,ldifluoroalkyl)-L-cysteine conjugates are not (11,12). 2-Bromo-2-chloro-1,1-difluoroethene is a halothane-derived 1,1-difluoroalkene that is apparently metabolized to the mercapturate S-(2-bromo-2-chloro-1,1-difluoroethyl)-iV-acetyl-L-cysteine (26,27). The 2-bromo-2-chloro-1,1-difluoroethene-derived conjugates S-(2-bromo-2-chloro-1, l-difluoroethyl)glutathione and S -(2-bromo-2-chloro-1,1difluoroethyl)-L-cysteine (BCDFC) undergo 8-lyasedependent bioactivation and are nephrotoxic in rats and cytotoxic in LLC-PKl cells (28).…”

Section: Introductionmentioning

confidence: 99%

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Finkelstein

Vamvakas²,

Bittner³

et al. 1994

Chem. Res. Toxicol.

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Glutathione and cysteine S-conjugates of several haloalkenes are nephrotoxic and cytotoxic. Chloroalkene-derived S-(1-chloroalkenyl)-L-cysteine conjugates, but not fluoroalkene-derived S-(2,2-dihalo-1,1-difluorethyl)-L-cysteine conjugates, are mutagenic in the Ames test, although both types of S-conjugates are cytotoxic and nephrotoxic. Recent studies showed that bromine-containing S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are mutagenic in the Ames test, thus challenging the generalization that S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates are not mutagenic. Hence a series of bromine-containing and bromine-lacking S-(2,2-dihalo-1,1-difluoroethyl)-L-cysteine conjugates was prepared, and their mutagenicity was assessed in the Ames test with Salmonella typhimurium TA2638 as the test strain. In addition, several indices of cytotoxicity, including cytotoxicity in LLC-PK1 cells, induction of Ca2+ release from pig kidney mitochondria, and DNA double-strand breaks in LLC-PK1 cells, were measured. The bromine-containing S-conjugates S-(2-bromo-2-chloro-1,1-difluoroethyl)-L- cysteine (BCD-FC), S-(2-bromo-1,1,2-trifluoroethyl)-L-cysteine (BTFC), and S-(2,2-dibromo-1,1-difluoroethyl)-L-cysteine (DBDFC) were mutagenic in the Ames test, whereas S-(2-chloro-1,1,2-trifluorethyl)-L-cysteine (CTFC), S-(2,2-dichloro-1,1-difluoroethyl)-L-cysteine (DCDFC), and S-(1,1,2,2-tetrafluoroethyl)-L-cysteine (TFC), which lack bromine, were not. BCDFC, BTFC, CTFC, DBDFC, and TFC were cytotoxic in LLC-PK1 cells, and their cytotoxicity was blocked by the cysteine conjugate beta-lyase inhibitor (aminooxy)acetic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

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Section: Introductionmentioning

confidence: 99%

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Finkelstein

Vamvakas²,

Bittner³

et al. 1994

Chem. Res. Toxicol.

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“…2-Bromo-2-chloro-1,1-difluoroethylene reacts readily and nonenzymatically with sulfur nucleophiles, such as GSH and cysteine, forming S-(2-bromo-2-chloro-1,1-difluoroethyl)-N-acetyl-L-cysteine, that is present in the urine of halothane-anesthetized humans (Wark et al, 1990).…”

Section: Bioactivation Of 2-bromo-2-chloro-11-difluoroethylenementioning

confidence: 99%

Glutathione Metabolism: Favorable Versus Unfavorable Effects

Cimino

Saija

2008

Oxidants in Biology

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The aim of this paper is to review current knowledge concerning the different perspectives that are actually investigated to better clarify the role of GSH in organism health.Glutathione (GSH) is widely found in all forms of life and plays an essential role especially in aerobic organisms. In animals, including humans, and in plants, GSH is the predominant non-protein thiol and acts as a redox buffer, in particular keeping with its own SH groups those of proteins in a reduced condition. Because of the cysteine residue, GSH is readily oxidized non-enzymatically to glutathione disulfide (GSSG) by electrophilic substances; GSSG is in turn reduced to GSH by the NADPH-dependent glutathione reductase. Cellular GSH concentrations are markedly reduced in response to oxidative stress and the GSH/GSSG ratio is often used as an indicator of the cellular redox state. Furthermore, GSH acts as an endogenous trapping for reactive intermediates derived from exogenous and endogenous chemicals preventing unwanted reactions of chemically reactive molecules with important cell constituents. In fact, GSH is able to form adducts with a wide range of reactive intermediates, such as quinoneimines, nitrenium ions, arene oxides, quinones, imine methides, Michael acceptors and 4-hydroxy-2-nonenal.Although GSH conjugation has been identified as an important detoxification reaction, other biological and/or toxic effects of some GSH-adducts have been described. For example, oxyeicosanoid GSH-adducts do not represent just inactivation products, but they can both retain or show novel biological activities. However, several papers describe the biotransformation and bioactivation of a range of nephrotoxic compounds, evidencing that this bioactivation is dependent on GSH S-conjugate formation and activation of cysteine S-conjugates by cysteine conjugate β-lyase. Furthermore, recent evidences show that GSH may conjugate to nitric oxide (NO) to form an S-nitroso-glutathione (GSNO) adduct. GSNO represents one of the major transport forms of NO in biological systems, may give rise to transnitrosation and S-thiolation reactions. GSNO has been shown to have several pharmacological activities, including the inhibition of platelet aggregation and a protective effect during the exposure of cells to oxidants. Finally, recent studies have also highlighted the ability of GSH and of its catabolites to promote oxidative processes, by participating in metal-ion-mediated reactions leading to formation of reactive oxygen species and free radicals.

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“…As indicated above, the terminal products of the biotransformation of bromine-lacking 1,1-difluoroalkene-derived cysteine S -conjugates are dihaloacetic acids. 1-Bromo-1-chloro-2,2-difluoroethene, a metabolite or decomposition product, or both, of the anesthetic halothane , is biotransformed to N -acetyl- S -(2-bromo-2-chloro-1,1-difluoroethyl)- l -cysteine in human subjects anesthetized with halothane , , indicating glutathione S -conjugate formation and processing. An investigation of the fate of S -(2-bromo-2-chloro-1,1-difluoroethyl)- l -cysteine in rat kidney homogenates and in a pyridoxal model system showed that glyoxylic acid rather than the expected bromochloroacetic acid is the terminal metabolite .…”

Section: -Halo-α-thiolactonesmentioning

confidence: 99%

Chemical Toxicology of Reactive Intermediates Formed by the Glutathione-Dependent Bioactivation of Halogen-Containing Compounds

Anders

2007

Chem. Res. Toxicol.

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The concept that reactive intermediate formation during the biotransformation of drugs and chemicals is an important bioactivation mechanism was proposed in the 1970s and is now accepted as a major mechanism for xenobiotic-induced toxicity. The enzymology of reactive intermediate formation as well as the characterization of the formation and fate of reactive intermediates are now well-established. The mechanism by which reactive intermediates cause cell damage and death is, however, still poorly understood. Although most xenobiotic-metabolizing enzymes catalyze the bioactivation of chemicals, glutathione-dependent biotransformation has been largely associated with detoxication processes, particularly mercapturic acid formation. Abundant evidence now shows that glutathione-dependent biotransformation constitutes an important bioactivation mechanism for halogen-containing drugs and chemicals and has for many compounds been implicated in their organ-selective toxicity and in their mutagenic and carcinogenic potential. The glutathione-dependent biotransformation of haloalkenes is the first step in the cysteine S-conjugate beta-lyase pathway for the bioactivation of nephrotoxic haloalkenes. This pathway has been a rich source of reactive intermediates, including thioacyl halides, alpha-chloroalkenethiolates, 3-halo-alpha-thiolactones, 2,2,3-trihalothiiranes, halothioketenes, and vinylic sulfoxides. Glutathione-dependent bioactivation of gem-dihalomethanes and 1,2-, 1,3-, and 1,4-dihaloalkanes leads to the formation of alpha-chlorosulfides, thiiranium ions, sulfenate esters, and tetrahydrothiophenium ions, respectively, and these reactions lead to reactive intermediate formation.

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A Urinary Cysteine-Halothane Metabolite: Validation and Measurement in Children

Cited by 18 publications

References 0 publications

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Structure-Mutagenicity and Structure-Cytotoxicity Studies on Bromine-Containing Cysteine S-Conjugates and Related Compounds

Glutathione Metabolism: Favorable Versus Unfavorable Effects

Chemical Toxicology of Reactive Intermediates Formed by the Glutathione-Dependent Bioactivation of Halogen-Containing Compounds

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