Cytochrome P-450-mediated metabolism of biphenyl and the 4-halobiphenyls

Abstract

The in vitro metabolism of biphenyl, 4-fluoro-, 4-chloro-, 4-bromo- and 4-iodobiphenyl by cytochrome P-450-dependent monooxygenases was investigated using hepatic microsomes from immature male rats pretreated with phenobarbitonc or 3-methylcholanthrene. The major route of metabolism of biphenyl and the 4-halobiphenyls was 4'-hydroxylation. i.e. para to the phenyl-phenyl bridge. The minor route of metabolism apparently changed from 2-hydroxylation for biphenyl (i.e. ortho to the phenyl-phenyl bridge) to 3-hydroxylation for all 4-halobiphenyls (i.e. ortho to the halogen). In marked contrast to biphenyl, the regioselectivity of 4-halobiphenyl metabolism was not altered by pretreatment of rats with either phenobarbitone or 3-methylcholanthrene. The overall rate of metabolism of 4-fluoro- and 4-bromobiphenyl to water-soluble metabolites increased 2-fold and 5- to 6-fold using microsomes from rats pretreated with phenobarbitone and 3-methylcholanthrene respectively. In contrast, the overall rates of metabolism of 4-chloro- and 4-iodobiphenyl were refractory to the inductive effects of phenobarbitone but were increased more than 10-fold following pretreatment with 3-methylcholanthrene. There was a correlation between the apparent binding affinities of microsomes from phenobarbitone-treated rats for biphenyl and the 4-halobiphenyls and their calculated log octanol/water partition coefficients (lipophilicity). However, the effects of the halogen substituents on the rates of metabolism of the 4-halobiphenyls by microsomes from control and induced rats did not correlate with their binding affinities or with any physiochemical differences between the fluoro, chloro, bromo and iodo substituents.