Influence of cytochrome P-450 type on the pattern of conjugation of 4-hydroxybiphenyl generated from biphenyl or 4-methoxybiphenyl.
The rate of production of 4-hydroxybiphenyl from 4-methoxybiphenyl in hepatocytes isolated from untreated rats was essentially identical to that from biphenyl in hepatocytes isolated from rats pretreated with beta-naphthoflavone at 40 mg/kg. Similar results were obtained using liver microsomes isolated from untreated or treated rats. The selective inhibition of these reactions by metyrapone, alpha-naphthoflavone and ethanol demonstrated that different forms of cytochrome P-450 are responsible for O-demethylation of 4-methoxybiphenyl in livers of untreated rats and 4-hydroxylation of biphenyl in livers of pretreated rats. The pattern of conjugation of 4-hydroxybiphenyl generated from biphenyl in hepatocytes isolated from pretreated rats was different from that for 4-hydroxybiphenyl generated from 4-methoxybiphenyl in hepatocytes isolated from untreated rats, there being a 60% decrease in sulphation measured after 60 min incubation with biphenyl. Glucuronidation of 4-hydroxybiphenyl was not affected. The sulphation of 4-hydroxybiphenyl added directly was significantly decreased in hepatocytes isolated from pretreated rats. The initial rate of glucuronidation of 4-hydroxybiphenyl added directly was not altered by the pretreatment, but there was a significant decrease in overall glucuronidation measured over a 60 min incubation. Similar results were obtained using liver slices. beta-Naphthoflavone added directly to liver slices significantly decreased the extent of sulphation of 4-hydroxybiphenyl but did not influence glucuronidation. There was evidence of a late decrease in biphenyl 4-hydroxylase activity in hepatocytes isolated from pretreated rats. It is concluded that the differences observed in the cellular metabolism of biphenyl and 4-methoxybiphenyl can be ascribed to competition between beta-naphthoflavone and/or its metabolites retained within the cells following pretreatment, and biphenyl and/or its metabolites for the pathways common to their metabolism. It is also concluded that the type of cytochrome P-450 involved in the generation of 4-hydroxybiphenyl does not, per se, influence the subsequent pattern of conjugation.
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001571:Benzoflavones / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D005965:Glucuronates / Q000378:metabolism; D020723:Glucuronic Acid; D006900:Hydroxylation; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008745:Methylation; D010090:Oxidoreductases, O-Demethylating / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013431:Sulfates / Q000378:metabolism; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D001713:Biphenyl Compounds; D005965:Glucuronates; D013431:Sulfates; D019324:beta-Naphthoflavone; C031475:4-methoxybiphenyl; D020723:Glucuronic Acid; D003577:Cytochrome P-450 Enzyme System; C019046:4-phenylphenol; D010090:Oxidoreductases, O-Demethylating; D001189:Aryl Hydrocarbon Hydroxylases; C019793:biphenyl-4-hydroxylase