Cytochrome P-450-dependent covalent binding of 1,1,2,2-tetrachloroethane in vitro.

Incubation of 1,1,2,2,-tetrachloro[1,2-14C]ethane with a reconstituted mono-oxygenase system or with intact rat liver microsomes led to the formation of a metabolite capable of binding covalently to proteins and other nucleophiles. The enzyme system responsible for metabolizing tetrachloroethane to both soluble and covalently bound metabolites was induced by phenobarbital or xylene but not by beta-naphthoflavone treatment. The only soluble metabolite detected upon incubation of tetrachloroethane with a reconstituted system was dichloroacetic acid, whereas microsomes produced both dichloroacetic acid and an alkali-labile adduct of dichloroacetic acid. Pronase digestion of the 14C-labeled microsomal proteins after incubation with 14C-tetrachloroethane indicated the presence of several derivatized amino acids, which were hydrolyzed by alkali to yield dichloroacetic acid. The putative active metabolite produced by the microsomes could be trapped with chloramphenicol base, yielding the corresponding dichloroacetyl derivative, chloramphenicol. The results are consistent with a scheme whereby 1,1,2,2-tetrachloroethane is metabolized by cytochrome P-450 to dichloroacetyl chloride, which can bind covalently to various nucleophiles or hydrolyze to dichloroacetic acid.