The effect of trichloroethylene on cytochrome P450 form-specific activities of mouse, rat and human microsomes.
Snawder JE; Huffmann C; Lipscomb J
Toxicologist 1995 Mar; 15(1):118
Trichloroethylene (TCE) is a commonly used industrial solvent and a frequent environmental contaminant; therefore exposure to TCE may frequently occur in certain human populations. TCE has been found to cause hepatocellular carcinoma when administered by gavage to B6C3F1 mice, but not rats; this observation implies that TCE is metabolized differently in the two species. As part of an investigation of TCE metabolism, we investigated the effect of TCE on form specific P450 activities in microsomes from mouse, rat and human. TCE (1000 ppm), added to the headspace of reaction vessels, inhibited CYP2El dependent activity (N-nitrosodimethylamine N-demethylase [DMN] and p-nitrophenol hydroxylase, [PNPOH]) in all three species and CYP3A activity (BROD) in mice and rats; TCE (1000 ppm) increased CYP1A1/1A2 activity (EROD and Phenacetin O-deethylase), and had no effect on CYP2A activity (coumarin hydroxylase). Inhibition kinetic studies using mouse microsomes demonstrated that TCE was a competitive inhibitor of PNPOH and BROD with Ki of 50 and 250ppm, respectively. Preincubation of microsomes with TCE and a source of NADPH resulted in decreased absorbance of CO-bound P450, which correlated with the NADPH-dependent uptake of TCE from the incubation-vessel headspace. This work demonstrates that TCE is likely metabolized by CYP2E1 in all three species and by CYP3A in mouse and rat, and that TCE can interact with other form-specific activities in ways other than inhibition.
Animal-studies; Laboratory-animals; Solvent-vapors; Solvents; Vapors; Fumes; Environmental-contamination; Carcinogens
The Toxicologist. Society of Toxicology 34th Annual Meeting, March 5-9,1995, Baltimore, Maryland