Covalent binding and inhibition of cytochrome P4502E1 by trichloroethylene

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Abstract
1. To investigate the effects of trichloroethylene on cytochrome P4502E1 (CYP2E1), an isozyme responsible for its metabolic activation, mice were treated with trichloroethylene and Western blot staining with both anti-dichloroacetyl and anti-CYP2E1 antisera detected acomigrating 50 kDaprotein band. There was adose-dependent increase in the intensity of the 50 kDa protein adduct stained immunochemically with antidichloroacetyl. 2. CYP2E1 enzyme activity was decreased from control levels in a dose-dependent manner in mice treated with 250-500 mg kg TRI. 3. Microsomal incubations with trichloroethylene resulted in covalent binding to several proteins including a 50 kDa adduct, which is in contrast with the selective binding to the 50 kDa protein observed in vivo. 4. CYP2E1 enzyme activity levels were significantly decreased following microsomal incubation with NADPH and trichloroethylene, and additionally there was a time- and NADPH- dependent decrease in enzyme activity indicating that trichloroethylene is a mechanism- based inhibitor of CYP2E1.