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Titolo:
Covalent alteration of the CYP3A4 active site: Evidence for multiple substrate binding domains
Autore:
Schrag, ML; Wienkers, LC;
Indirizzi:
Pharmacia Corp, Global Metab & Invest Sci, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 Invest Sci, Kalamazoo, MI 49007 USA
Titolo Testata:
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
fascicolo: 1, volume: 391, anno: 2001,
pagine: 49 - 55
SICI:
0003-9861(20010701)391:1<49:CAOTCA>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN-LIVER-MICROSOMES; CYTOCHROME-P450 3A4; IN-VITRO; WARFARIN-FLUCONAZOLE; DRUG-INTERACTION; METABOLISM; INHIBITION; COOPERATIVITY; ACTIVATION; KINETICS;
Keywords:
triazolam; midazolam; testosterone; CYP3A4; mechanism-based inactivation; substrate-dependent;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
32
Recensione:
Indirizzi per estratti:
Indirizzo: Wienkers, LC Pharmacia Corp, Global Metab & Invest Sci, 301 Henrietta St, Kalamazoo, MI49007 USA Pharmacia Corp 301 Henrietta St Kalamazoo MI USA 49007 07 USA
Citazione:
M.L. Schrag e L.C. Wienkers, "Covalent alteration of the CYP3A4 active site: Evidence for multiple substrate binding domains", ARCH BIOCH, 391(1), 2001, pp. 49-55

Abstract

The inhibition of CYP3A4-mediated oxidation of triazolam and testosterone was assessed in the presence of a selection of known CYP3A4 substrates and inhibitors. Under experimental conditions where the Michaelis-Menten model predicts substrate-independent inhibition ([S] = K-m), results yielded substrate-dependent inhibition. Moreover, when the same experimental design wasextended to a group of structurally similar flavonoids it was observed that flavanone, flavone, 3-hydroxyflavone, and 6-hydroxyflavone (10 muM) activated triazolam metabolism, but inhibited testosterone hydroxylation. In additional studies, residual CYP3A4 activity toward testosterone and triazolamhydroxylation was measured after pretreatment with the CYP3A4 mechanism based inhibitor, midazolam. After midazolam preincubation, CYP3A4 Gp-hydroxylase activity was reduced by 47% while, in contrast, triazolam hydroxylationwas reduced by 75%. These results provide physical evidence, which supports the hypothesis that the active site of CYP3A4 contains spatially distinctsubstrate-binding domains within the enzyme active site. (C) 2001 AcademicPress.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/01/20 alle ore 10:05:42