Rat liver microsomal induction of the oxidation of drugs and alcohols, and sodium dodecyl sulfate-gel profiles after in vivo treatment with pyrazole or 4-methylpyrazole.
Studies were carried out to characterize and compare the effects of pyrazole and 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase, on microsomal oxidation of a variety of drugs and alcohols. Whereas pyrazole treatment of rats (200 mg/kg b.wt./day for 2 days) resulted in an enrichment of a cytochrome P-450 isozyme with a molecular weight of about 52,000 on sodium dodecyl sulfate gels, 4-methylpyrazole treatment resulted in increased amounts of two or three P-450 isozymes, one of which appeared to be similar to the isozyme increased by pyrazole. The qualitative induction of two or three isozymes of P-450 as shown by sodium dodecyl sulfate-gel electrophoresis correlates with a 2-fold increase in total content of P-450 by 4-methylpyrazole. Microsomes from the pyrazole-treated rats displayed increased activity (expressed per milligram of protein or per nanomole of P-450) with aniline, p-nitroanisole, dimethylnitrosamine (low-Km enzyme) and ethanol as substrates, but not with aminopyrine, ethoxycoumarin or dimethylnitrosamine (high-Km enzyme). A stereochemical preference for the (+)-2-butanol isomer over the (-)-isomer was also observed. Kinetic experiments indicated that the pyrazole treatment increased the Vmax for ethanol, aniline and (+)-2-butanol oxidation. These properties are similar to those found with microsomes from chronic ethanol-fed rats and suggest that, in rats, pyrazole and ethanol may induce similar isozymes of P-450, and that the former may serve as a convenient model for the latter. This comparable induction between ethanol and pyrazole is in contrast to results using imidazole, which has been reported by others not to induce an alcohol-preferring P-450 in rats.(ABSTRACT TRUNCATED AT 250 WORDS)
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G
Krikun
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DE
Feierman
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Cederbaum
D000438:Alcohols / Q000378:metabolism* / Q000494:pharmacology; D000632:Aminopyrine / Q000378:metabolism; D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D000440:Butanols / Q000378:metabolism; D003374:Coumarins / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000378:metabolism; D000077604:Fomepizole; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D008970:Molecular Weight; D010084:Oxidation-Reduction; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012967:Sodium Dodecyl Sulfate; D013237:Stereoisomerism
D000438:Alcohols; D000814:Aniline Compounds; D000440:Butanols; D003374:Coumarins; D007527:Isoenzymes; D004364:Pharmaceutical Preparations; D011720:Pyrazoles; D000632:Aminopyrine; C043958:2-butanol; C017299:7-ethoxycoumarin; D012967:Sodium Dodecyl Sulfate; D000431:Ethanol; C031280:pyrazole; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; C023650:aniline