标题：Use of Kinetic and Mechanistic Data in Species Extrapolation of Bioactivation: Cytochrome P-450 Dependent Trichloroethylene Metabolism at Occupationally Relevant Concentrations
摘要：Use of Kinetic and Mechanistic Data in Species Extrapolation of Bioactivation: Cytochrome P-450 Dependent Trichloroethylene Metabolism at Occupationally Relevant Concentrations: John C. LlPSOCOMB, et al. United States Air Force, Armstrong Laboratory. Toxicology Division -Trichloroethylene (TRl) is an industrial solvent and environmental contaminant; therefore exposure to TRl occurs in diverse human populations. TRl causes hepatocellular carcinoma in B6C3F1 mice, but not rats; this suggests that TRI may be metabolized differently in the two species. We investigated the metabolism of TRl and the eftect of TRl on enzymatic activities indicative of specific cytochrome P450 (CYP) forms in hepatic microsomes from mice, rats and humans. Studies in microsomes estimated Michaelis-Menten kinetic parameters by saturation analysis. Km values were 35.4, 55.5 and 24.6 pM and Vmax values were 5, 425, 4, 826 and 1, 440 pmol/min/mg in pooled mouse, rat and human microsomes, respectively. TRl (1, OOO ppm) inhibited CYP2E1 dependent activity in all three species and BROD activity in mice and rats; TRl (1, OOO ppm) increased CYP1A1/1A2 activity, and had no effect on CYP2A activity. Inhibition studies with mouse hepatic microsomes demonstrated that TRl was a competitive inhibitor of CYP2E1, with Kj Of 50 ppm. TRl noncompetitively inhibited CYP2B-dependent activities in the rat and mouse. Preincubation of microsomes with TRl and NADPH decreased the absorbence of CO-bound CYP in all three species, but the dose-dependence was most evident in mouse hepatic microsomes. These results have quantified the interspecies difference in CYP-dependent TRl bioactivation and indicate that under both equivalent and occupationally relevant (hepatic) exposure conditions the human is at less risk of forming toxic CYP-derived TRl metabolites.
