COVALENT BINDING AND INHIBITION OF CYTOCHROME P4502E1 BY TRICHLOROETHYLENE

1. To investigate the effects of trichloroethylene on cytochrome P4502 E1 (CYP2E1), an isozyme responsible for its metabolic activation, mice were treated with trichloroethylene and Western blot staining with bo th anti-dichloroacetyl and anti-CYP2E1 antisera detected a comigrating 50 kDa protein band. There was a dose-dependent increase in the inten sity of the 50 kDa protein adduct stained immunochemically with anti-d ichloroacetyl. 2. CYP2E1 enzyme activity was decreased from control le vels in a dose-dependent manner in mice treated with 250-500 mg/kg TRI . 3. Microsomal incubations with trichloroethylene resulted in covalen t binding to several proteins including a 50 kDa adduct, which is in c ontrast with the selective binding to the 50 kDa protein observed in v ivo. 4. CYP2E1 enzyme activity levels were significantly decreased fol lowing microsomal incubation with NADPH and trichloroethylene, and add itionally there was a time- and NADPH-dependent decrease in enzyme act ivity indicating that trichloroethylene is a mechanism-based inhibitor of CYP2E1.