Characterization of the chemical reactivity and nephrotoxicity of N-acetyl-S-(1,2-dichlorovinyl)-l-cysteine sulfoxide, a potential reactive metabolite of trichloroethylene

Abstract

N-Acetyl-S-(1,2-dichlorovinyl)-L-cysteine (NA-DCVC) has been detected in the urine of humans exposed to trichloroethylene and its related sulfoxide, N-acetyl-S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (NA-DCVCS), has been detected as hemoglobin adducts in blood of rats dosed with S-(1,2-dichlorovinyl)-L-cysteine (DCVC) or S-(1,2-dichlorovinyl)-L-cysteine sulfoxide (DCVCS). Because the in vivo nephrotoxicity of NA-DCVCS was unknown, in this study, male Sprague-Dawley rats were dosed (i.p.) with 230 µmol/kg b.w. NA-DCVCS or its potential precursors, DCVCS or NA-DCVC. At 24 h post treatment, rats given NA-DCVC or NA-DCVCS exhibited kidney lesions and effects on renal function distinct from those caused by DCVCS. NA-DCVC and NA-DCVCS primarily affected the cortico-medullary proximal tubules (S2–S3 segments) while DCVCS primarily affected the outer cortical proximal tubules (S1–S2 segments). When NA-DCVCS or DCVCS was incubated with GSH in phosphate buffer pH 7.4 at 37°C, the corresponding glutathione conjugates were detected, but NA-DCVC was not reactive with GSH. Because NA-DCVCS exhibited a longer half-life than DCVCS and addition of rat liver cytosol enhanced GSH conjugate formation, catalysis of GSH conjugate formation by the liver could explain the lower toxicity of NA-DCVCS in comparison with DCVCS. Collectively, these results provide clear evidence that NA-DCVCS formation could play a significant role in DCVC, NA-DCVC, and trichloroethylene nephrotoxicity. They also suggest a role for hepatic metabolism in the mechanism of NA-DCVC nephrotoxicity.

Metabolism and Toxicity of Trichloroethylene and Tetrachloroethylene in Cytochrome P450 2E1 Knockout and Humanized Transgenic Mice

“…We did observe an increase in KIM-1 staining in PCE-treated mice, showing that kidney is a target tissue in the mouse. It has been postulated that the bio-activation of TCVC and NAcTCVC, catalyzed by renal b lyase or other enzymes such as flavin monooxygenase and CYP3A, is a critical step for nephrotoxicity of PCE (Irving et al, 2013;Lash et al, 1994). It is likely that CYP2E1 may also play a role in sulfoxidation of cysteine and n-acetyl cysteine conjugates of PCE, as it was shown that CYP2E1 is involved in sulfoxidation of S-methyl N, N-diethylthiolcarbamate (Madan et al, 1995) and diethyldithiocarbamate methyl ester (Madan et al, 1998).…”

Characterization of inter-tissue and inter-strain variability of TCE glutathione conjugation metabolites DCVG, DCVC, and NAcDCVC in the mouse

“…These findings are consistent with reports that in the absence of hepatic metabolism of GSH conjugates, PERC is more cytotoxic than TCE to isolated kidney cells (Lash et al, 2007), and that DCVC is less nephrotoxic than TCVC in vivo (Birner et al, 1997). However, kidney cancer hazard evidence in humans is more potent for TCE than PERC (Guha et al, 2012), indicating that bioactivation to downstream reactive sulfoxides, DCVCSO and NAcDCVCSO, may be most critical part of cancer etiology in the kidneys (Irving et al, 2013; Lash et al, 1994). It is also plausible that lower levels of DCVC and NAcDCVC, as compared to those of TCVC and NAcTCVC, are the product of a higher conversion rate to their corresponding sulfoxides, a process mediated by hepatic cytochrome P450 3A enzymes (Werner et al, 1996).…”

Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene

“…Subsequently, TCVC can be detoxified via N-acetylation to form N-acetyl-S-(1,2,2-trichlorovinyl)cysteine (NAcTCVC). Both TCVC and NAcTCVC can further undergo metabolic activation to generate reactive sulfoxides, which may contribute to the kidney effects of PERC (Irving et al. 2013).…”