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Titolo:
Triazolam substrate inhibition: Evidence of competition for heme-bound reactive oxygen within the CYP3A4 active site
Autore:
Schrag, ML; Wienkers, LC;
Indirizzi:
Pharmacia Corp, Drug Metab Res, Kalamazoo, MI 49007 USA Pharmacia Corp Kalamazoo MI USA 49007 Metab Res, Kalamazoo, MI 49007 USA
Titolo Testata:
DRUG METABOLISM AND DISPOSITION
fascicolo: 1, volume: 29, anno: 2001,
pagine: 70 - 75
SICI:
0090-9556(200101)29:1<70:TSIEOC>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN LIVER-MICROSOMES; RECOMBINANT CYTOCHROME-P450 3A4; IN-VITRO; ALPHA-NAPHTHOFLAVONE; P450 REDUCTASE; METABOLISM; MIDAZOLAM; OXIDATION; KINETICS; BINDING;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
31
Recensione:
Indirizzi per estratti:
Indirizzo: Wienkers, LC Pharmacia Corp, Drug Metab Res, 301 Henrietta St,7265-300-313, Kalamazoo, MI 49007 USA Pharmacia Corp 301 Henrietta St,7265-300-313 Kalamazoo MI USA 49007
Citazione:
M.L. Schrag e L.C. Wienkers, "Triazolam substrate inhibition: Evidence of competition for heme-bound reactive oxygen within the CYP3A4 active site", DRUG META D, 29(1), 2001, pp. 70-75

Abstract

In human liver microsomes, triazolam is principally metabolized by CYP3A4 to form two metabolites, 1'-hydroxytriazolam (1'OHTz) and 4-hydroxytriazolam (4OHTz). The velocity of 1'OHTz formation was found to decrease at highertriazolam concentrations (> 200 muM), indicative of "substrate inhibition". Coincubation of [C-14] triazolam with authentic metabolite standards of either 1'OHTz or 4OHTz up to 30 muM did not significantly inhibit the rate of [C-14]1'OHTz formation. The effects of secondary compounds on triazolam oxidation were shown to be product-specific, producing either activation or inhibition depending on the triazolam metabolite monitored. When human liver microsomes were supplemented with exogenous human cytochrome b(5), it wasobserved that substrate inhibition was attenuated and the resulting increase in 1'OHTz formation, relative to control (nonsupplemented) incubations, corresponded to a decrease in the ratio of 4OHTz to 1'OHTz. In contrast, when cofactor (e.g., 100 muM NADPH) was rate limiting, the metabolite ratio (4OHTz/1'OHTz) was markedly increased over the entire substrate concentration range (0.5-1000 muM). To explain these kinetic observations, a two-site binding model is proposed in which triazolam is hypothesized to bind within the CYP3A4 active site in spatially distinct orientations, which may lead to the formation of either the 1'-hydroxytriazolam or 4-hydroxytriazolam. Differential inhibition/activation is consistent with this two-site model andsubstrate inhibition is hypothesized to result from competition between the two sites for reactive oxygen.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/01/20 alle ore 01:04:12