Metabolism of chloroethanes by rat liver nuclear cytochrome P-450.
1,2-Dichloroethane, 1,1,1-trichloroethane and 1,1,2,2-tetrachloroethane appear to be metabolized by hepatic nuclear 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 nuclear preparations. The major metabolites of the chlorinated ethanes from hepatic microsomal cytochrome P-450, viz. chloroacetaldehyde from 1,2-dichloroethane, 2,2,2-trichloroethanol from 1,1,1-trichloroethane, and dichloroacetic acid from 1,1,2,2-tetrachloroethane, were also produced from the three chloroalkanes by hepatic nuclear 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 nuclear 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 nuclei 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 nuclei 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 nuclei, the metabolism of 1,2-dichloroethane and 1,1,2,2-tetrachloroethane by nuclear cytochrome P-450 may in part mediate the mutagenicity and carcinogenicity of parent compounds.
D000818:Animals; D001711:Biotransformation; D002458:Cell Fractionation; D002467:Cell Nucleus / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004980:Ethane / Q000031:analogs & derivatives* / Q000378:metabolism; D005025:Ethylene Dichlorides / Q000378:metabolism*; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D014240:Trichloroethanes / Q000378:metabolism*
D005025:Ethylene Dichlorides; D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; C015530:1,1,2,2-tetrachloroethane; C024565:ethylene dichloride; D003577:Cytochrome P-450 Enzyme System; D004980:Ethane; D010634:Phenobarbital