Cytochrome P-450-mediated metabolism of biphenyl and the 4-halobiphenyls.
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 phenobarbitone 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.
D000818:Animals; D001713:Biphenyl Compounds / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D010105:Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains
D001713:Biphenyl Compounds; C030552:4-iodobiphenyl; C034950:4-fluorobiphenyl; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D010105:Oxygenases; C034949:4-bromobiphenyl; C006983:4-chlorobiphenyl; D010634:Phenobarbital