<i>S</i>-(1,2,2-Trichlorovinyl)-l-cysteine Sulfoxide, a Reactive Metabolite of<i>S</i>-(1,2,2-Trichlorovinyl)-l-cysteine Formed in Rat Liver and Kidney Microsomes, Is a Potent Nephrotoxicant

Elfarra, Adnan A.; Krause, Renee J.

doi:10.1124/jpet.107.120444

Cited by 24 publications

(10 citation statements)

References 28 publications

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“…One important limitation of this method, however, is its focus on proximal metabolites of the GSH conjugation pathway and not on some of the more reactive and toxic downstream metabolites such as TCVC sulfoxide (Elfarra and Krause 2007). Still, the method reported herein will be applicable to further toxicokinetic studies of PERC and inform human health assessments of this ubiquitous environmental toxicant.…”

Section: Resultsmentioning

confidence: 99%

“…1,2,2-trichlorovinylthiol can spontaneously form a reactive thioketene which can adduct to DNA and proteins (IARC 2014). PERC metabolites from the GSH conjugation pathway are cytotoxic in vitro (Lash et al 2002, Birner et al 1997, Irving and Elfarra 2013) and nephrotoxic in vivo (Birner et al 1997, Elfarra and Krause 2007). They are also mutagenic (Vamvakas et al 1989b, Vamvakas et al 1989a, Irving and Elfarra 2013).…”

Section: Introductionmentioning

confidence: 99%

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Simultaneous detection of the tetrachloroethylene metabolites S-(1,2,2-trichlorovinyl) glutathione, S-(1,2,2-trichlorovinyl)-L-cysteine, and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in multiple mouse tissues via ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry

Luo

Cichocki

McDonald

et al. 2017

Journal of Toxicology and Environmental Health, Part A

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Tetrachloroethylene (perchloroethylene; PERC) is a high-production volume chemical and a ubiquitous environmental contaminant that is hazardous to human health. Toxicity of PERC is mediated through oxidative and glutathione conjugation metabolites. The conjugation of PERC by glutathione-s-transferase to generate S-(1,2,2-trichlorovinyl) glutathione (TCVG), which is subsequently metabolized to form S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) is of special importance to human health. Specifically, TCVC can be metabolized to N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) which is excreted through urine, or to electrophilic metabolites that are nephrotoxic and mutagenic. Little is known about toxicokinetics of TCVG, TCVC, and NAcTCVC as analytical methods for simultaneous determination of these metabolites in tissues have not yet been reported. Hence, an ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry-based method was developed for analysis of TCVG, TCVC, and NAcTCVC in liver, kidney, serum, and urine. The method is rapid, sensitive, robust, and selective for detection all three analytes in every tissue examined, with limits of detection ranging from 1.8–68.2 femtomoles on column, depending on the analyte and tissue matrix. This method can be applied to quantify levels of TCVG, TCVC, and NAcTCVC in tissues from mice treated with PERC (10 to 1000 mg/kg, orally) with limits of quantitation of 1–2.5 pmol/g in liver, 1–10 pmol/g in kidney, 1–2.5 pmol/mL in serum, and 2.5–5 pmol/mL in urine. This method is useful for further characterization of the glutathione conjugative pathway of PERC in vivo and improved understanding of PERC toxicity.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Simultaneous detection of the tetrachloroethylene metabolites S-(1,2,2-trichlorovinyl) glutathione, S-(1,2,2-trichlorovinyl)-L-cysteine, and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine in multiple mouse tissues via ultra-high performance liquid chromatography electrospray ionization tandem mass spectrometry

Luo

Cichocki

McDonald

et al. 2017

Journal of Toxicology and Environmental Health, Part A

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“…DCVC can be oxidized by flavin-containing monooxygenases (FMOs) (Ripp et al, 1997; Krause et al, 2003) and TCVC can be oxidized by FMOs or cytochrome P450s (Ripp et al, 1997). DCVCS (Lash et al, 1994) and TCVCS (Elfarra and Krause, 2007) have both been demonstrated to be more nephrotoxic than the precursor cysteine S -conjugates, likely due to their ability to act as direct-acting toxicants through covalent reactions with sulfhydryl-containing molecules. Recently, DCVCS-hemoglobin adducts and cross-links have been detected in rats given DCVC, providing evidence for in vivo metabolism of DCVC to DCVCS (Barshteyn and Elfarra, 2009).…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity of the cysteine S-conjugate sulfoxides of trichloroethylene and tetrachloroethylene in the Ames test

Irving

Elfarra

2013

Toxicology

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The nephrotoxicity and nephrocarcinogenicity of trichloroethylene (TCE) and tetrachloroethylene (PCE) are believed to be mediated primarily through the cysteine S-conjugate β-lyase-dependent bioactivation of the corresponding cysteine S-conjugate metabolites S-(1,2-dichlorovinyl)-L-cysteine (DCVC) and S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), respectively. DCVC and TCVC have previously been demonstrated to be mutagenic by the Ames Salmonella mutagenicity assay, and reduction in mutagenicity was observed upon treatment with the β-lyase inhibitor aminooxyacetic acid (AOAA). Because DCVC and TCVC can also be bioactivated through sulfoxidation to yield the potent nephrotoxicants S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS) and S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide (TCVCS), respectively, the mutagenic potential of these two sulfoxides was investigated using the Ames S. typhimuriumTA100 mutagenicity assay. The results show both DCVCS and TCVCS were mutagenic, and TCVCS exhibited 3-fold higher mutagenicity than DCVCS. However, DCVCS and TCVCS mutagenic activity was approximately 700-fold and 30-fold lower than DCVC and TCVC, respectively. DCVC and DCVCS appeared to induce toxicity in TA100, as evidenced by increased microcolony formation and decreased mutant frequency above threshold concentrations. TCVC and TCVCS were not toxic in TA100. The toxic effects of DCVC limited the sensitivity of TA100 to DCVC mutagenic effects and rendered it difficult to investigate the effects of AOAA on DCVC mutagenic activity. Collectively, these results suggest that DCVCS and TCVCS exerted a definite but weak mutagenicity in the TA100 strain. Therefore, despite their potent nephrotoxicity, DCVCS and TCVCS are not likely to play a major role in DCVC or TCVC mutagenicity in this strain.

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“…The mercapturic acids are cytotoxic in rat renal epithelial cells, and their cytotoxicity is reduced by the -lyase inhibitor (aminooxy)acetic acid, indicating hydrolysis of the mercapturic acids and -lyasecatalyzed bioactivation of the formed cysteine S-conjugates (176); (aminooxy)acetic acid failed to reduce the cytotoxicity of the corresponding mercapturic acid sulfoxides, indicating that they are direct-acting electrophiles. Recent studies show, however, that both FMO and P450 are involved in the sulfoxidation of S-(trichlorovinyl)-L-cysteine (178). (Fluoromethoxy)-1,1,3 The role of vinylic cysteine S-conjugate-derived sulfoxides in the nephrotoxicity and cytotoxicity of cysteine S-conjugates merits further investigation to establish the role of cysteine S-conjugate S-oxidation by FMO or P450 in the nephrotoxicity of vinylic cysteine S-conjugates.…”

Section: Vinylic Sulfoxidesmentioning

confidence: 96%

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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S-(1,2,2-Trichlorovinyl)-l-cysteine Sulfoxide, a Reactive Metabolite ofS-(1,2,2-Trichlorovinyl)-l-cysteine Formed in Rat Liver and Kidney Microsomes, Is a Potent Nephrotoxicant

Cited by 24 publications

References 28 publications

Mutagenicity of the cysteine S-conjugate sulfoxides of trichloroethylene and tetrachloroethylene in the Ames test

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

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