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Titolo:
Mechanism-based inactivation of CYP2C11 by diclofenac
Autore:
Masubuchi, Y; Ose, A; Horie, T;
Indirizzi:
Chiba Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Inage Ku, Chiba 2638522, Japan Chiba Univ Chiba Japan 2638522 harmaceut, Inage Ku, Chiba 2638522, Japan
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 9, volume: 29, anno: 2001,
pagine: 1190 - 1195
SICI:
0090-9556(200109)29:9<1190:MIOCBD>2.0.ZU;2-X
Fonte:
ISI
Lingua:
ENG
Soggetto:
ANTIINFLAMMATORY DRUG DICLOFENAC; CULTURED RAT HEPATOCYTES; LIVER PROTEIN ADDUCTS; METABOLIC-ACTIVATION; IDENTIFICATION; GLUCURONIDE; TOXICITY; BINDING; 3A4;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
25
Recensione:
Indirizzi per estratti:
Indirizzo: Horie, T Chiba Univ, Grad Sch Pharmaceut Sci, Dept Biopharmaceut, Inage Ku, 1-33 Yayoi Cho, Chiba 2638522, Japan Chiba Univ 1-33 Yayoi Cho Chiba Japan 2638522 iba 2638522, Japan
Citazione:
Y. Masubuchi et al., "Mechanism-based inactivation of CYP2C11 by diclofenac", DRUG META D, 29(9), 2001, pp. 1190-1195

Abstract

It has been known that diclofenac is biotransformed into chemically reactive metabolites, which bind covalently to liver microsomal proteins, including cytochrome P450 enzyme(s). We have investigated the ability and selectivity of diclofenac to inactivate P450 enzymes. Preincubation of microsomes of untreated rats with diclofenac in the presence of NADPH resulted in time-dependent loss of testosterone 2 alpha- and 16 alpha -hydroxylation activities. No effect of the preincubation was observed on ethoxyresorufin O-deethylase, pentoxyresorufin O-depentylase, or testosterone 6 beta -hydroxylation activity. The time-dependent decreases in testosterone 2 alpha- and 16 alpha -hydroxylation activities followed the pseudo-first order kinetics and were saturable with increasing diclofenac concentrations. Reduced glutathione was not capable of protecting against the decrease in the enzyme activities. These data establish that a mechanism-based inactivation of CYP2C11 occurs during the oxidative metabolism of diclofenac. The diclofenac concentrations required to achieve the half-maximal rate of inactivation (K-i) were3 to 4 muM, which were close to K-m for the low-K-m components for diclofenac 4'- and 5-hydroxylation activities (7.29 and 4.43 muM, respectively). Anti-CYP2C11 IgG inhibited diclofenac 4'- and 5-hydroxylation activities, indicating that CY1P2C11 is a major isozyme responsible for these aromatic oxidations. The preincubation of microsomes with 4'- or 5-hydroxydiclofenac did not cause a decrease in testosterone 2 alpha- or 16 alpha -hydroxylationactivity, suggesting that neither of the primary metabolites is a precursor of the metabolite that inactivates CYP2C11. Therefore, a highly reactive intermediate(s) inactivating CYP2C11, probably arene-oxide, appears to be generated during the process of diclofenac 4'- and/or 5-hydroxylation. Diclofenac metabolism in human liver microsomes did not cause inactivation of CYP2C9, a major isozyme involved in diclofenac 4'-hydroxylation. Because the human microsomes have high diclofenac 4'-hydroxylation but not 5-hydroxylation activity, importance of the latter pathway in the inactivation is suggested.

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Documento generato il 05/04/20 alle ore 01:05:04