Biphenyl metabolism by rat liver microsomes: regioselective effects of inducers, inhibitors, and solvents.
Examination of the regioselective metabolism of biphenyl was explored as a means of characterizing different forms of cytochrome P-450 in microsomal and purified mono-oxygenase systems. In the present study the 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 primarily induced 2- and 3-hydroxylation, the latter most dramatically. 3-Methylcholanthrene pretreatment induced 2- and 3-hydroxylation to similar extents. The 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 is indicated by the regioselective effects of the solvents and the inhibitors. The 3-methylcholanthrene-dependent increases in 2- and 3-hydroxylation appear 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. The phenobarbital-dependent increases in 2- and 3-hydroxylation appear due to the induction of two forms of cytochrome P-450, as indicated by different changes in sensitivity to the effects of dimethyl sulfoxide and 7,8-benzoflavone. The results indicate that examination of the regioselectivity of biphenyl metabolism is a useful approach for characterizing microsomal mono-oxygenases, and they suggest that the approach may also be useful in the characterization of purified mono-oxygenase systems.
D000096:Acetone / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001571:Benzoflavones / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D000432:Methanol / Q000494:pharmacology; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D000096:Acetone; D001189:Aryl Hydrocarbon Hydroxylases; D001571:Benzoflavones; D001713:Biphenyl Compounds; D003577:Cytochrome P-450 Enzyme System; D004121:Dimethyl Sulfoxide; D007093:Imidazoles; D000432:Methanol; D008748:Methylcholanthrene; D010634:Phenobarbital; C010574:biphenyl; C017062:1-benzylimidazole; C011512:alpha-naphthoflavone; C021775:biphenyl-2-hydroxylase; C019793:biphenyl-4-hydroxylase