Induction of rabbit hepatic microsomal cytochrome P-450 by imidazole: enhanced metabolic activity and altered substrate specificity.

Abstract:

: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.

journal_name

Arch Biochem Biophys

authors

Kaul KL,Novak RF

doi

10.1016/0003-9861(84)90220-0

subject

Has Abstract

pub_date

1984-12-01 00:00:00

pages

470-81

issue

2

eissn

0003-9861

issn

1096-0384

pii

0003-9861(84)90220-0

journal_volume

235

pub_type

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