Chloroethanes: their metabolism by hepatic cytochrome P-450 in vitro

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Abstract
1,1,1- and 1,1,2-trichloroethane and 1,1,2,2-tetra-chloroethane stimulate CO- inhibitable NADPH oxidation by hepatic microsomes. Incubation of the chloroethanes, hepatic microsomes, an NADPH-generating system and EDTA results in the production of chlorinated metabolites. Both NADPH oxidation and metabolite production are inhibited by CO, SKF 525A and/or metyrapone. The induction of cytochrome P-450 with phenobarbital enhances the binding and metabolism of the chloroalkanes, while the induction of cytochrome P-448 with β-napthoflavone does not. 1,1,1-trichloroethane is converted to 2,2,2-trichloroethanol by hepatic microsomal cytochrome P-450, while the major metabolites of 1,1,2-trichloroethane and 1,1,2,2-tetrachloroethane from this enzyme system are mono- and dichloroacetate, respectively. Mechanisms for the production of these metabolites are suggested. The relative mutagenic and carcinogenic potentials of the three chloroethanes are considered with respect to their relative extents of metabolism and their proposed metabolic pathways.