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 methylpyrazoie, potent inhibitors of alcohol dehydrogenase, cata lyzed the oxidation of ethanol and 2‐butanoJ at rates 2–3‐fold highe than saline controls. Time course experiments and dose‐response experiments indicated that an increase in the microsomal oxidatioi 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 oxidatior 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 ma) induce an alcohol‐preferring P‐450 isozyme. By contrast, the 4‐methylpyrazoie 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 arte aminopyrine was primarily due to the increase in content of P‐45C produced by the 4‐methylpyrazole treatment Binding spectra wrtti dimethyl sulfoxide and 2‐butanol were also observed after 4‐methylpyrazole treatment; however, the 2‐butanol‐binding spectrum was a modified type I spectrum, not type 2. Taken as a whole, these results indicate that pyrazole and 4‐methylpyrazole treatment can affect the microsomal mixed function oxidase system and the oxidation of alcohols by microsomes, and that there are differences in the interaction of these compounds with microsomes.