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

Andrew Parkinson, Stephen Safe

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1849-1856
Number of pages8
JournalBiochemical pharmacology
Volume31
Issue number10
DOIs
StatePublished - May 15 1982

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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