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

Irving, Roy M.; Elfarra, Adnan A.

doi:10.1016/j.tox.2013.02.003

Cited by 17 publications

(10 citation statements)

References 29 publications

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“…It was found to be mutagenic in S. typhimurium (strains TA100, TA2638, and TA98) using the Ames assay in the absence of S9 [154], and in S. typhimurium strain TA2638 with kidney subcellular fractions for metabolic activation [155]. A recent study confirmed these findings [156]. The genotoxicity of DCVC is further supported by the predominantly positive results in other available in vitro and in vivo assays.…”

Section: Gsh Conjugation Of Tcementioning

confidence: 82%

See 1 more Smart Citation

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Lash

Chiu²,

Guyton

et al. 2014

Mutation Research/Reviews in Mutation Research

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Metabolism is critical for the mutagenicity, carcinogenicity, and other adverse health effects of trichloroethylene (TCE). Despite the relatively small size and simple chemical structure of TCE, its metabolism is quite complex, yielding multiple intermediates and end-products. Experimental animal and human data indicate that TCE metabolism occurs through two major pathways: cytochrome P450 (CYP)-dependent oxidation and glutathione (GSH) conjugation catalyzed by GSH S-transferases (GSTs). Herein we review recent data characterizing TCE processing and flux through these pathways. We describe the catalytic enzymes, their regulation and tissue localization, as well as the evidence for transport and inter-organ processing of metabolites. We address the chemical reactivity of TCE metabolites, highlighting data on mutagenicity of these end-products. Identification in urine of key metabolites, particularly trichloroacetate (TCA), dichloroacetate (DCA), trichloroethanol and its glucuronide (TCOH and TCOG), and N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NAcDCVC), in exposed humans and other species (mostly rats and mice) demonstrates function of the two metabolic pathways in vivo. The CYP pathway primarily yields chemically stable end-products. However, the GST pathway conjugate S-(1,2-dichlorovinyl)glutathione (DCVG) is further processed to multiple highly reactive species that are known to be mutagenic, especially in kidney where in situ metabolism occurs. TCE metabolism is highly variable across sexes, species, tissues and individuals. Genetic polymorphisms in several of the key enzymes metabolizing TCE and its intermediates contribute to variability in metabolic profiles and rates. In all, the evidence characterizing the complex metabolism of TCE can inform predictions of adverse responses including mutagenesis, carcinogenesis, and acute and chronic organ-specific toxicity.

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Section: Gsh Conjugation Of Tcementioning

confidence: 82%

“…DCVCS was found to be weakly mutagenic in S. typhimurium strain TA100 in the Ames salmonella mutagenicity assay [156]. DCVCS mutagenic activity was approximately 700-fold lower than that of DCVC.…”

Section: Gsh Conjugation Of Tcementioning

confidence: 99%

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Lash

Chiu²,

Guyton

et al. 2014

Mutation Research/Reviews in Mutation Research

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“…TCVG can be converted in the kidney through a two-step metabolic reaction to yield S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC). TCVC is a metabolite of high concern as it can be converted to cytotoxic and genotoxic electrophiles (Vamvakas et al, 1987(Vamvakas et al, , 1988(Vamvakas et al, , 1989Irving and Elfarra, 2013) and can be detoxified to the mercapturate N-acetyl-S-(1,2,2-trichlorvinyl)-L-cysteine (NAcTCVC), which is a urinary metabolite of PERC in humans. However, little is known about the effects of NAFLD on these PERC metabolism pathways.…”

Section: Introductionmentioning

confidence: 99%

Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice

Cichocki

Furuya

Konganti

et al. 2017

J Pharmacol Exp Ther

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Lifestyle factors and chronic pathologic states are important contributors to interindividual variability in susceptibility to xenobiotic-induced toxicity. Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent condition that can dramatically affect chemical metabolism. We examined the effect of NAFLD on toxicokinetics of tetrachloroethylene (PERC), a ubiquitous environmental contaminant that requires metabolic activation to induce adverse health effects. Mice (C57Bl/6J, male) were fed a low-fat diet (LFD), high-fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, steatosis, or nonalcoholic steatohepatitis (NASH), respectively. After 8 weeks, mice were orally administered a single dose of PERC (300 mg/kg) or vehicle (aqueous Alkamuls-EL620) and euthanized at various time points (1-36 hours). Levels of PERC and its metabolites were measured in blood/serum, liver, and fat. Effects of diets on liver gene expression and tissue: air partition coefficients were evaluated. We found that hepatic levels of PERC were 6-and 7.6-fold higher in HFD-and MCD-fed mice compared with LFD-fed mice; this was associated with an increased PERC liver:blood partition coefficient. Liver and serum C max for trichloroacetate (TCA) was lower in MCD-fed mice; however, hepatic clearance of TCA was profoundly reduced by HFD or MCD feeding, leading to TCA accumulation. Hepatic mRNA/protein expression and ex vivo activity assays revealed decreased xenobiotic metabolism in HFD-and MCD-, compared with LFD-fed, groups. In conclusion, experimental NAFLD was associated with modulation of xenobiotic disposition and metabolism and increased hepatic exposure to PERC and TCA. Underlying NAFLD may be an important susceptibility factor for PERC-associated hepatotoxicity.

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“…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%

“…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). Therefore, determining tissue-specific levels of these metabolites is critical to establishing concentration-response relationships for PERC exposure and effects (Cichocki et al 2016).…”

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

Cited by 17 publications

References 29 publications

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Trichloroethylene biotransformation and its role in mutagenicity, carcinogenicity and target organ toxicity

Impact of Nonalcoholic Fatty Liver Disease on Toxicokinetics of Tetrachloroethylene in Mice

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