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 0 to 300 mg per kg body wt per day for three 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 mg microsomal protein, but not per nmol cytochrome P-450. Therefore, 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.
D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D000077604:Fomepizole; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D011720:Pyrazoles / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013053:Spectrophotometry
D011720:Pyrazoles; D000077604:Fomepizole; D003577:Cytochrome P-450 Enzyme System