Interaction of pyrazole and 4-methylpyrazole with hepatic microsomes: effect on cytochrome P-450 content, microsomal oxidation of alcohols, and binding spectra.

Abstract

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)

• Authors: D E Feierman, A I Cederbaum
• Journal: Alcoholism, clinical and experimental research (Alcohol Clin Exp Res) 1985 Sep-Oct Vol. 9 Issue 5 Pg. 421-8 ISSN: 0145-6008 [Print] England
• PMID: 3933374 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Alcohols
• Butanols
• Pyrazoles
• Aminopyrine
• 2-butanol
• Ethanol
• Fomepizole
• Cytochrome P-450 Enzyme System
• NADPH-Ferrihemoprotein Reductase
• Dimethyl Sulfoxide

Topics

• Alcohols (metabolism)
• Aminopyrine (metabolism)
• Animals
• Butanols (metabolism)
• Cytochrome P-450 Enzyme System (analysis)
• Dimethyl Sulfoxide (metabolism)
• Ethanol (metabolism)
• Fomepizole
• Male
• Microsomes, Liver (drug effects, metabolism)
• NADPH-Ferrihemoprotein Reductase (metabolism)
• Pyrazoles (pharmacology)
• Rats
• Rats, Inbred Strains