Induction of rabbit hepatic microsomal cytochrome P-450 by imidazole: enhanced metabolic activity and altered substrate specificity.
Pretreatment of rabbits with imidazole resulted in a twofold increase in hepatic microsomal cytochrome P-450 content, with the apparent induction of two or more distinct forms of the cytochrome [K. K. Hajek and R. F. Novak (1982) Biochem. Biophys. Res. Commun. 108, 664-672]. The metabolic properties of imidazole-induced microsomes have been compared to those of uninduced, phenobarbital- and beta-naphthoflavone-induced preparations. Metabolic activity was enhanced as a consequence of increased P-450 content and as a result of the presence of different forms of the cytochrome. When rates were expressed per nanomole P-450 the following were observed: (a) p-nitroanisole O-demethylation was comparable in all preparations; (b) N,N-dimethylaniline N-demethylation was comparable in imidazole- and beta-naphthoflavone-induced, and uninduced microsomes; (c) polycyclic aromatic hydrocarbon hydroxylase activity was approximately twofold greater in imidazole-induced relative to phenobarbital-induced microsomes, but was only one-half that of beta-naphthoflavone-induced microsomes; and (d) metabolism of N,N-dimethylnitrosamine was enhanced fivefold, alcohol oxidation increased three- to fivefold, and aniline hydroxylation was threefold greater in imidazole-induced microsomes compared to phenobarbital- or beta-naphthoflavone-induced preparations. Eadie-Scatchard analysis yielded a single Km value for dimethylnitrosamine N-demethylase activity in imidazole-induced microsomes; in contrast, both high- and low-Km values were obtained for phenobarbital- or beta-naphthoflavone-induced microsomal preparations. Dimethylnitrosamine N-demethylase activity was P-450 dependent; neither flavin monooxygenase nor monoamine oxidase appeared to contribute significantly to dimethylnitrosamine metabolism. Dimethyl sulfoxide was a competitive inhibitor of dimethylnitrosamine N-demethylase activity in imidazole-, phenobarbital-, and beta-naphthoflavone-induced microsomes. Dimethyl sulfoxide competitively inhibited ethanol oxidation in imidazole-induced microsomes; it was a noncompetitive inhibitor of ethanol oxidation in phenobarbital- or beta-naphthoflavone-induced microsomes.
D000438:Alcohols / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000378:metabolism; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001564:Benzo(a)pyrene / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004128:Dimethylnitrosamine / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008995:Monoamine Oxidase / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D011817:Rabbits; D013379:Substrate Specificity
D000438:Alcohols; D000814:Aniline Compounds; D000840:Anisoles; D007093:Imidazoles; D001564:Benzo(a)pyrene; C015157:N,N-dimethylaniline; C029899:imidazole; D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; D008995:Monoamine Oxidase; C005306:4-nitroanisole; D004128:Dimethylnitrosamine; C023650:aniline; D004121:Dimethyl Sulfoxide