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Titolo:
Inactivation of rat cytochrome P450 2D enzyme by a further metabolite of 4-hydroxypropranolol, the major and active metabolite of propranolol
Autore:
Narimatsu, S; Arai, T; Masubuchi, Y; Horie, T; Hosokawa, M; Ueno, K; Kataoka, H; Yamamoto, S; Ishikawa, T; Cho, AK;
Indirizzi:
Okayama Univ, Lab Hlth Chem, Okayama 7008530, Japan Okayama Univ OkayamaJapan 7008530 Lab Hlth Chem, Okayama 7008530, Japan Okayama Univ, Fac Pharmaceut Sci, Lab Biomol Sci, Okayama 7008530, Japan Okayama Univ Okayama Japan 7008530 ab Biomol Sci, Okayama 7008530, Japan Chiba Univ, Dept Biopharmaceut, Chiba 2638522, Japan Chiba Univ Chiba Japan 2638522 Dept Biopharmaceut, Chiba 2638522, Japan Chiba Univ, Dept Biochem Pharmacol, Chiba 2638522, Japan Chiba Univ Chiba Japan 2638522 t Biochem Pharmacol, Chiba 2638522, Japan Chiba Univ, Dept Geriat Pharmacol & Therapeut, Chiba 2638522, Japan Chiba Univ Chiba Japan 2638522 armacol & Therapeut, Chiba 2638522, Japan Chiba Univ, Grad Sch Pharmaceut Sci, Dept Med Organ Chem, Chiba 2638522, Japan Chiba Univ Chiba Japan 2638522 Dept Med Organ Chem, Chiba 2638522, Japan Univ Calif Los Angeles, Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA90024 USA Univ Calif Los Angeles Los Angeles CA USA 90024 Los Angeles, CA90024 USA
Titolo Testata:
BIOLOGICAL & PHARMACEUTICAL BULLETIN
fascicolo: 9, volume: 24, anno: 2001,
pagine: 988 - 994
SICI:
0918-6158(200109)24:9<988:IORCP2>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; DEBRISOQUINE 4-HYDROXYLASE; MONOOXYGENASE ACTIVITIES; COVALENT BINDING; OWN METABOLISM; IMPAIRMENT; ISOZYMES; CYP2D6; SPECIFICITY; ENANTIOMERS;
Keywords:
4-hydroxypropranolol; enzyme inactivation; rat CYP2D enzyme; bunitrolol; quinine; 1,4-naphthoquinone;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Narimatsu, S Okayama Univ, Lab Hlth Chem, 2-5-1 Shikata Cho, Okayama 7008530, Japan Okayama Univ 2-5-1 Shikata Cho Okayama Japan 7008530 , Japan
Citazione:
S. Narimatsu et al., "Inactivation of rat cytochrome P450 2D enzyme by a further metabolite of 4-hydroxypropranolol, the major and active metabolite of propranolol", BIOL PHAR B, 24(9), 2001, pp. 988-994

Abstract

Repetitive administration of propranolol (PL) in rats decreases the activities of cytochrome P450 (CY-P) 2D enzyme(s) in hepatic microsomes. We examined the properties of 4-hydroxypropranolol (4-OH-PL) as an inactivator of rat liver microsomal CYP2D enzyme(s) using bunitrolol (BTL) 4-hydroxylation and PL 5- and 7-hydroxylations as indices of CYP2D enzyme activity. Rat microsomal BTL 4-hydroxylase activity was inhibited by the addition of 4-OH-PLto the incubation medium. The inhibition was greater after preincubation of microsomes with 4-OH-PL in the presence of NADPH than in its absence. Thetype of inhibition kinetics of BTL 4-hydroxylase by 4-OH-PL was changed from a competitive type to a noncompetitive type by the preincubation. The inhibition by 4-OH-PL was changed from a competitive ty of rat liver microsomal PL 5- and 7-hydroxylases by 4-OH-PL was blocked efficiently by co-incubation with quinine, a typical inhibitor of rat CYP2D enzyme(s), or to a lesser extent by BTL. However, quinidine, a diastereomer of quinine, did not significantly protect against the enzyme inactivation. The protective capacities of the substrate and inhibitors reflected their affinities for rat CYP2D enzyme(s). BTL hydroxylase was not affected by either 1,4-naphthoquinone or 1,4-dihydroxynaphthalene which are possible metabolites of 4-OH-PL. These results provide further evidence to support the notion that PL is biotransformed by rat CYP2D enzyme(s) to 4-OH-PL, which is further oxidized to a chemically reactive metabolite in the active site. The inactivation of CYP is likely the result of covalent binding of the reactive species to an aminoacid residue of the active site.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 30/05/20 alle ore 15:18:58