S-(1,2,2-trichlorovinyl)-L-cysteine sulfoxide, a reactive metabolite of S-(1,2,2-Trichlorovinyl)-L-cysteine formed in rat liver and kidney microsomes, is a potent nephrotoxicant.
Previously, we have provided evidence that cytochromes P450 (P450s) and flavin-containing monooxygenases (FMOs) are involved in the oxidation of S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC) in rabbit liver microsomes to yield the reactive metabolite TCVC sulfoxide (TCVCS). Because TCVC is a known nephrotoxic metabolite of tetrachloroethylene, the nephrotoxic potential of TCVCS in rats and TCVCS formation in rat liver and kidney microsomes were investigated. At 5 mM TCVC, rat liver microsomes formed TCVCS at a rate nearly 5 times higher than the rate measured with rat kidney microsomes, whereas at 1 mM TCVC only the liver activity was detectable. TCVCS formation in liver and kidney microsomes was dependent upon the presence of NADPH and was inhibited by the addition of methimazole or 1-benzylimidazole, but not superoxide dismutase, catalase, KCN, or deferoxamine, consistent with the involvement of both FMOs and P450s. Rats given TCVCS at 230 micromol/kg i.p. exhibited acute tubular necrosis at 2 and 24 h after treatment, and they had elevated blood urea nitrogen levels at 24 h, whereas TCVC was a much less potent nephrotoxicant than TCVCS. Furthermore, pretreatment with aminooxyacetic acid enhanced TCVC toxicity. In addition, reduced nonprotein thiol concentrations in the kidney were decreased by nearly 50% 2 h after TCVCS treatment compared with saline-treated rats, whereas the equimolar dose of TCVC had no effect on kidney nonprotein thiol status. No significant lesions or changes in nonprotein thiol status were observed in liver with either TCVC or TCVCS. Collectively, the results suggest that TCVCS may play a role in TCVC-induced nephrotoxicity.
Elfarra
Adnan A
AA
Department of Comparative Biosciences and Center for Molecular and Environmental Toxicology, University of Wisconsin, Madison, Wisconsin, USA. elfarra@svm.vetmed.wisc.edu
Krause
Renee J
RJ
D000410:Alanine Transaminase / Q000097:blood; D000625:Aminooxyacetic Acid / Q000494:pharmacology; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D003545:Cysteine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006029:Glycosuria / Q000652:urine; D007093:Imidazoles / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008713:Methimazole / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism*; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000032:analysis; D013454:Sulfoxides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005723:gamma-Glutamyltransferase / Q000652:urine
D001786:Blood Glucose; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007093:Imidazoles; C110705:S-(1,2,2-trichlorovinyl)-L-cysteine; D013438:Sulfhydryl Compounds; D013454:Sulfoxides; D000625:Aminooxyacetic Acid; C017062:1-benzylimidazole; D008713:Methimazole; D003577:Cytochrome P-450 Enzyme System; D005723:gamma-Glutamyltransferase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003545:Cysteine