INCREASED CONTENT OF CYTOCHROME-P-450 AND 4-METHYLPYRAZOLE BINDING SPECTRUM AFTER 4-METHYLPYRAZOLE TREATMENT

4-Methylpyrazole is a potent inhibitor of alcohol dehydrogenase and of ethanol metabolism. In vitro, 4-methylpyrazole was shown to inhibit microsomal oxidation of drugs and alcohols. Treatment of rats with 4-methylpyrazole at doses ranging from 1-300 mg/kg body wt per day for 3 days resulted in a dose-dependent increase in the content of liver microsomal cytochrome P-450. There was no change in the activity of NADPH-cytochrome P-450 reductase. 4-Methylpyrazole interacted with control microsomes to produce a type II binding spectrum, with a peak at 429 nm, and a trough at 392 nm. The magnitude of this spectral change was increased after 4-methylpyrazole treatment. Kinetic experiments indicated that the 4-methylpyrazole treatment lowered the dissociation constant (ks) for 4-methylpyrazole. The maximal binding (Vs) was increased when expressed per milligram microsomal protein, but not per nanomole cytochrome P-450. 4-Methylpyrazole treatment can affect the microsomal mixed-function oxidase system in several ways, including binding to P-450 as well as inducing P-450.