Azoreduction of N,N-dimethyl-4-aminoazobenzene (DAB) by rat hepatic microsomes. Selective induction by clofibrate.
Metabolism of the hepatocarcinogen, N,N-dimethyl-4-aminoazobenzene (DAB) by rat liver microsomes proceeds via N-demethylation, ring hydroxylation, and azoreduction. DAB azoreduction was induced in microsomes from rats treated with the hypolipidemic drug, clofibrate, whereas oxidative metabolism of the carcinogen was inhibited. In contrast, treatment with nafenopin, another hypolipidemic drug, inhibited microsomal azoreduction of DAB, whereas oxidative pathways were only slightly affected. No direct effect of either drug on azoreductase activity was observed. Both drugs markedly induced microsomal laurate hydroxylation. DAB azoreduction was increased slightly in microsomes from rats treated with beta-naphthoflavone while treatment with phenobarbital led to partial inhibition. Pretreatment with isosafrol or pregnenolone-16 alpha-carbonitrile did not significantly alter DAB reduction. Metyrapone, added in vitro, inhibited microsomal DAB azoreductase activity only in phenobarbital-treated microsomes, whereas alpha-napthoflavone and SKF 525-A inhibited activity in control and all induced microsomes. DAB azoreduction proceeds readily in air and is not sensitive to carbon monoxide. Neither clofibrate nor nafenopin affected NADPH-cytochrome c reductase activity. It is concluded that clofibrate-induced azoreductase activity is probably attributable to a specific isoform of cytochrome P-450 which can be distinguished from those which catalyze oxidative pathways of DAB or laurate hydroxylation.
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D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002994:Clofibrate / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D006900:Hydroxylation; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism*; D009255:Nafenopin / Q000494:pharmacology; D010084:Oxidation-Reduction; D011335:Proadifen / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D019324:beta-Naphthoflavone; D004124:p-Dimethylaminoazobenzene / Q000378:metabolism*
D001571:Benzoflavones; D009255:Nafenopin; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D004124:p-Dimethylaminoazobenzene; D011335:Proadifen; D002994:Clofibrate