Abstract

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)