Metabolism of chloroethanes by rat liver nuclear cytochrome P-450

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Abstract
1, 2-DichJoroethane, 1, 1, 1-trichloroethane and 1, 1, 2, 2-tetra-chloroethane appear to be metabolized by hepatic nudear cytochrome P-450. All of these compounds are converted to chlorinated metabolites after incubation with hepatic nuclei and an NADPH-generating system plus EDTA, with the omission of any component eliminating metabolite production. In addition, CO, an inhibitor of cytochrome P-450, diminished the production of the chlorinated metabolites by hepatic nudear preparations. The major metabolites of the chlorinated ethanes from hepatic mtcrosomal cytochrome P-450, viz. chloroacetaldehyde from 1, 2-dichloroethane, 2, 2, 2-trichloroethanol from 1, 1, 1-trichloroethane, and dichloroacetic add from 1, 1, 2, 2-tetrachloroethane, were also produced from the three chloroaikanes by hepatic nudear cytochrome P-450. The levels of the metabolites produced were 65, 0.09 and 4.4 nmol/nmol cytochrome P-450/60 min. It is proposed that the pathways for the formation of these metabolites by hepatic nudear cytochrome P-450 are as for their production by hepatic microsomal cytochrome P-450. Chloral hydrate was produced from 1, 1, 1-trichloroethane by hepatic nudei plus NADPH, but not by hepatic microsomes. The presence of reactive species or transient enzyme bound intermediates in the pathways for the cytochrome P-450 dependent metabolism of the chloroethanes in hepatic nudei is suggested by the observation that nuclear cytochrome P-450 is degraded in the presence of the chloroethanes in a NADPH dependent process which is inhibited by CO. It is proposed that, although the cytochrome P-450 dependent metabolism of the chloroethanes in microsomes can greatly exceed that in nudei, the metabolism of 1, 2-dichloroethane and 1, 1, 2, 2-tetrachloroethane by nudear cytochrome P-450 may in part mediate the mutagenidty and carcinogenidty of parent compounds.