BIPHENYL METABOLISM IN ISOLATED RAT HEPATOCYTES - EFFECT OF INDUCTION AND NATURE OF CONJUGATES

Biphenyl is metabolised by untreated isolated rat hepatocytes via hydroxylation at the 4-position followed by conjugation with sulphate and glucuronic acid. At a substrate concentration of 70 μM, the major metabolite produced is 4-hydroxybiphenyl sulphate. Hydroxylation at the 2- and 3-positions also occurs but to a much smaller extent. Induction in vivo by phenobarbitone or 3-methylcholanthrene results in a marked increase in the rate of the initial hydroxylation and a change in the pattern of the conjugates with 70 μM biphenyl. In the induced state 4-hydroxybiphenyl glucuronide is the dominant metabolite, 4-hydroxybiphenyl sulphate production being similar to controls. Two- and 3-hydroxylation of biphenyl in isolated rat hepatocytes is markedly increased by 3-methylcholanthrene pretreatment, but is unaffected by phenobarbitone pretreatment. Studies on the metabolism of two of the primary metabolites of biphenyl, 2- and 4-hydroxybiphenyl, in untreated isolated rat hepatocyte suspensions revealed that whereas at low (7 μM) concentrations of both metabolites, sulphate conjugation was predominant, with increasing substrate concentration the contribution of the glucuronidation pathway was elevated to such an extent that it became the predominant conjugating pathway at the highest concentrations used (140 μM). The reasons for the lag between the 'initial hydroxylation' and the onset of glucuronic acid conjugation of 4-hydroxybiphenyl were investigated. Attempts were made to eliminate this lag by prior incubations of the cells with 4-methylumbelliferone in an effort to activate the conjugating enzymes responsible. Glucuronidation of 4-hydroxybiphenyl is activated significantly by this treatment, whereas sulphation of 4-hydroxybiphenyl is not. © 1978.