In vitro metabolism of 4-chlorobiphenyl by control and induced rat liver microsomes.
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abstract
The in vitro metabolism, mechanism of metabolism, and macromolecular binding of a monochlorobiphenyl component of commercial polychlorinated biphenyls (PCB) have been investigated. 4-Chlorobiphenyl was metabolized by rat liver microsomes in the presence of NADPH to yield a major metabolite, 4'-chloro-4-biphenylol, and a number of minor metabolites. The metabolism of deuterium-labeled 4-chlorobiphenyl proceeded with the NIH shift of the isotope and no observed isotope effect thus indicating the intermediacy of an arene oxide. Noninduced rat liver microsomes mediated the covalent binding between the 4-chlorobiphenyl and 4'-chloro-4-biphenylol substrates and endogenous microsomal protein. Prior in vivo administration of a commericial PCB preparation, Aroclor 1248 (Monsanto Chemical Co., containing 48 percent by weight of chlorine), resulted in an induced microsomal preparation which significantly increased the substrate-protein binding. The effect of various inhibitors on protein binding was investigated. Aroclor 1248 induced microsomes mediated binding of 4-chlorobiphenyl to endogenous and exogenous nucleic acids, indicating a possible mechanism for the previously reported mutagenic action of this chlorobiphenyl. The spectral properties of Aroclor 1248 induced cytochrome P-450 were investigated and compared with the pentobarbital-induced cytochrome fraction.
