Interaction of pyrazole and 4-methylpyrazole with hepatic microsomes: effect on cytochrome P-450 content, microsomal oxidation of alcohols, and binding spectra.
Microsomes isolated from rats treated with either pyrazole or 4-methylpyrazole, potent inhibitors of alcohol dehydrogenase, catalyzed the oxidation of ethanol and 2-butanol at rates 2-3-fold higher than saline controls. Time course experiments and dose-response experiments indicated that an increase in the microsomal oxidation of alcohols could be observed 24 hr after a single treatment with 200 mg/kg body weight of either pyrazole or 4-methylpyrazole, and after 2 or 3 days of treatment with 50 mg/kg of either of these compounds. The pyrazole treatment did not change the activity of NADPH-cytochrome P-450 reductase, the content of cytochrome P-450, or the oxidation of aminopyrine. Hence, microsomal oxidation of alcohols was increased by the pyrazole treatment whether results were expressed "per mg of protein" or "per nmol of P-450." Microsomes from the pyrazole-treated rats displayed an increase in binding spectrum with ethanol as the substrate as compared to controls, as well as type 2 binding spectrum with dimethyl sulfoxide and 2-butanol. These results suggest the possibility that pyrazole may induce an alcohol-preferring P-450 isozyme. By contrast, the 4-methylpyrazole treatment, besides increasing the oxidation of alcohols, also increased the oxidation of aminopyrine and the content of cytochrome P-450. The increase in the oxidation of alcohols and aminopyrine was primarily due to the increase in content of P-450 produced by the 4-methylpyrazole treatment. Binding spectra with dimethyl sulfoxide and 2-butanol were also observed after 4-methylpyrazole treatment; however, the 2-butanol-binding spectrum was a modified type 1 spectrum, not type 2.(ABSTRACT TRUNCATED AT 250 WORDS)
D000438:Alcohols / Q000378:metabolism*; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D000440:Butanols / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis*; D004121:Dimethyl Sulfoxide / Q000378:metabolism; D000431:Ethanol / Q000378:metabolism; D000077604:Fomepizole; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D000438:Alcohols; D000440:Butanols; D011720:Pyrazoles; D000632:Aminopyrine; C043958:2-butanol; D000431:Ethanol; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System; D009251:NADPH-Ferrihemoprotein Reductase; D004121:Dimethyl Sulfoxide