Pyrazole is known to interact with and to induce
cytochrome P-450 IIE1. Since
pyrazole is oxidized by rat liver microsomes to
4-hydroxypyrazole, and several of the actions of
pyrazole have been ascribed to its metabolite, experiments were conducted to evaluate the interactions of
4-hydroxypyrazole with microsomes, and to compare these to
pyrazole itself. Rats were injected with doses of
4-hydroxypyrazole ranging from 2 to 100 mg/kg
body weight/day for 2 days. A slight increase of total
cytochrome P-450 was observed at low doses, followed by a decrease at higher concentrations.
NADPH-cytochrome P-450 reductase activity was not affected. The oxidation of
aniline or
dimethylnitrosamine was increased about 50% by the
4-hydroxypyrazole treatment; however, this extent of increase was much less than that produced by
pyrazole treatment. In vitro,
4-hydroxypyrazole produced a type II binding spectrum with microsomes, with a peak at about 425 nm and a trough at about 395 nm. The affinity for
4-hydroxypyrazole was increased from a value of about 0.60 mM in control microsomes to a value of about 0.40 mM in microsomes from
pyrazole-treated rats. These values are 2-fold greater than those observed with
pyrazole as the
ligand.
4-Hydroxypyrazole inhibited the microsomal oxidation of
ethanol; kinetics of inhibition were mixed. The apparent KI for
4-hydroxypyrazole inhibition of
ethanol oxidation by microsomes was about 4 mM, which is about an order of magnitude greater than that for
pyrazole. The in vivo and in vitro interactions of
4-hydroxypyrazole with microsomes appear to be similar to those described for
pyrazole; however, these interactions are considerably less effective than those of the parent
drug,
pyrazole. Thus, although some actions of
pyrazole may be due to the metabolite
4-hydroxypyrazole, it appears that the induction of P-450 IIE1 and the in vitro interactions of
pyrazole with microsomes is not likely to be mediated by prior metabolism of
pyrazole to
4-hydroxypyrazole.