BIPHENYL METABOLISM BY RAT-LIVER MICROSOMES - REGIOSELECTIVE EFFECTS OF INDUCERS, INHIBITORS, AND SOLVENTS

  • 1 January 1981
    • journal article
    • research article
    • Vol. 9  (3) , 212-218
Abstract
Examination of the regioselective metabolism of biphenyl was explored to characterize different forms of cytochrome P-450 in microsomal and purified monooxygenase systems. Effects of the inducers phenobarbital and 3-methylcholanthrene, the inhibitors 7,8-benzoflavone and 1-benzylimidazole and the solvents methanol, acetone and dimethyl sulfoxide on the 2-, 3- and 4-hydroxylation of biphenyl and the O-deethylation of 7-ethoxycoumarin by rat liver microsomes were examined. Phenobarbital pretreatment induced 2- and 3-hydroxylation, the latter most dramatically. 3-Methylcholanthrene pretreatment induced 2- and 3-hydroxylation to similar extents. Inhibitors and solvents had regioselective effects on biphenyl metabolism that were characteristic of the uninduced, phenobarbital-induced and 3-methylcholanthrene-induced microsomes. The presence of multiple forms of cytochrome P-450 in uninduced microsomes was indicated by the regioselective effects of the solvents and inhibitors. 3-Methylcholanthrene-dependent increases in 2- and 3-hydroxylation were due to induction of a single form of cytochrome P-450, as indicated by similar dose-response relationships and similar changes in sensitivity to the inhibitors. Phenobarbital-dependent increases in 2- and 3-hydroxylation were due to the induction of 2 forms of cytochrome P-450, as indicated by different changes in sensitivity to the effects of dimethyl sulfoxide and 7,8-benzoflavone. Examination of the regioselectivity of biphenyl metabolism was a useful approach for characterizing microsomal monooxygenases and this approach may also be useful in the characterization of purified monooxygenase systems.