title: Reductive metabolism of 1,1,1,2-tetrachloroethane and related chloroethanes by rat liver microsomes.
abstract: The susceptibility of polychlorinated ethanes to reductive metabolism was evaluated by measuring the amount of each compound consumed during anaerobic incubations with rat live microsomes; 1,1,1,2-tetrachloroethane, pentachloroethane and hexachloroethane were metabolized extensively, 1,1,1,2-tetrachloroethane and the trichloroethanes were metabolized very slowly and the dichloroethanes were not metabolized at a detectable rate. The electron affinity of the chloroethanes was determined by measuring electrochemical half-wave reduction potentials. Chloroethanes with an E1/2 of - 1.35 V or less negative were reduced readily in microsomes while those with an E1/2 equal to or more negative than -1.90 V were not good substrates for enzymatic reduction. Metabolites produced from 1,1,1,2-tetrachloroethane in vitro were 1,1-dichloroethylene (DCE) and 1,1,2-trichloroethane (TCEA) and the ratio DCE/TCEA was about 25:1. These conversions were NADPH-dependent and were inhibited by air, CO and metyrapone. In the presence of SKF 525-A, DCE formation was inhibited by 47%. Microsomes from untreated or beta-naphthoflavone-treated rats were 70-90% less active than microsomes from phenobarbital-treated rats. The Km was 0.50 mM and the Vmax was 66 nmol min-1 mg-1 protein for DCE formation. The results are consistent with the proposal that 1,1,1,2-tetrachloroethane is reduced by hepatic cytochrome(s) P-450 to a free radical intermediate which, for the most part, remains closely associated with the enzyme, is reduced further and undergoes beta-elimination of a chloride ion to form DCE. The occurrence of this reductive pathway in vivo was demonstrated by the quantitation of DCE and TCEA in blood from rats treated with 1,1,1,2-tetrachloroethane.
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D001711:Biotransformation; D003067:Coenzymes / Q000378:metabolism; D004000:Dichloroethylenes / Q000378:metabolism; D004563:Electrochemistry; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004980:Ethane / Q000031:analogs & derivatives* / Q000378:metabolism; D006843:Hydrocarbons, Chlorinated / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D014240:Trichloroethanes / Q000378:metabolism
chemical_list: D003067:Coenzymes; D004000:Dichloroethylenes; D004791:Enzyme Inhibitors; D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; C031336:1,1,1,2-tetrachloroethane; C029297:vinylidene chloride; C024567:1,1,2-trichloroethane; D004980:Ethane