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.