Document Detail

Comparison of the interaction of pyrazole and its metabolite 4-hydroxypyrazole with rat liver microsomes.
MedLine Citation:
PMID:  1976058     Owner:  NLM     Status:  MEDLINE    
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.
L A Clejan; A I Cederbaum
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  18     ISSN:  0090-9556     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:    1990 Jul-Aug
Date Detail:
Created Date:  1990-10-19     Completed Date:  1990-10-19     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  393-7     Citation Subset:  IM    
Department of Biochemistry, Mount Sinai School of Medicine, New York, NY 10029.
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MeSH Terms
Aniline Hydroxylase / metabolism
Cytochrome P-450 Enzyme System / biosynthesis
Enzyme Induction / drug effects
Ethanol / metabolism
Microsomes, Liver / metabolism*
Mixed Function Oxygenases / metabolism
NADPH-Ferrihemoprotein Reductase / metabolism
Pyrazoles / metabolism*
Rats, Inbred Strains
Grant Support
Reg. No./Substance:
0/Pyrazoles; 4843-98-5/4-hydroxypyrazole; 64-17-5/Ethanol; 9035-51-2/Cytochrome P-450 Enzyme System; EC 1.-/Mixed Function Oxygenases; EC 1.14.14.-/Aniline Hydroxylase; EC Reductase

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