Cytochrome P450-dependent metabolism of trichloroethylene in rat kidney

The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was stu died in microsomes from liver and kidney homogenates and from isolated rena l proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite consistently detected a nd was used as a measurement of P450-dependent metabolism of Tri. Pretreatm ent of rats with pyridine increased CH formation in both liver and kidney m icrosomes, whereas pretreatment of rats with clofibrate increased CH format ion only in kidney microsomes. Pyridine increased CYP2E1 expression in both liver and kidney microsomes, whereas clofibrate had no effect on hepatic b ut increased renal CYP2E1 and CYP2C11 protein levels. These results suggest a role for CYP2E1 in both the hepatic and renal metabolism of Tri and a ro le for CYP2C11 in the renal metabolism of Tri. Studies with the general P45 0 inhibitor SKF-525A and the CYP2E1 competitive substrate chlorzoxazone pro vided additional support for the role of CYP2E1 in both tissues. CH formati on was higher in PT cells than in DT cells and was time and reduced nicotin amide adenine dinucleotide phosphate (NADPH) dependent. However, pretreatme nt of rats with either pyridine or clofibrate had no effect on CYP2E1 or CY P2C11 protein levels or on CH formation in isolated cells, These data show for the first time that Tri can be metabolized to at least one of its P450 metabolites in the kidneys and quantitate the effect of P450 induction on T ri metabolism in the rat kidney.