Influence of cytochrome P-450 type on the pattern of conjugation of 4-hydroxybiphenyl generated from biphenyl or 4-methoxybiphenyl

Abstract

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.

Influence of substrate concentration on the phase I and phase II metabolism of 4-methoxybiphenyl by rat isolated hepatocytes

“…It can be suggested from these data that this unconjugated 4-OHBP acts as the 'pool' of aglycone available for glucuronidation, a suggestion which is consistent with the temporal relationship of the attainment of the peak level of unconjugated 4-OHBP with the lag in onset of glucuronidation of 4-OHBP observed in the course of metabolism of 4-MBP by rat isolated hypatocytes (Paterson and Fry 1985). This would be expected if UDP-glucuronosyltransferase were acting as a low-affinity enzyme.…”