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Titolo:
Topological alteration of the CYP3A4 active site by the divalent cation Mg2+
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: 10, volume: 28, anno: 2000,
pagine: 1198 - 1201
SICI:
0090-9556(200010)28:10<1198:TAOTCA>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; METABOLISM; KINETICS; RAT;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
19
Recensione:
Indirizzi per estratti:
Indirizzo: Wienkers, LC Pharmacia Corp, Drug Metab Res, 301 Henrietta St, Kalamazoo, MI 49007 USA Pharmacia Corp 301 Henrietta St Kalamazoo MI USA 49007 07 USA
Citazione:
M.L. Schrag e L.C. Wienkers, "Topological alteration of the CYP3A4 active site by the divalent cation Mg2+", DRUG META D, 28(10), 2000, pp. 1198-1201

Abstract

Phenyldiazene reacted with lymphoblast-expressed CYP3A4 to give a stable phenyl-iron complex that could be induced to rearrange in situ producing approximately equal amounts of four N-phenyl- protoporphyrin IX isomers (N-B:N-A:N-C:N-D, 01:01:02:02). In the presence of 10 mM MgCl2, the formation profile of the protoporphyrin isomers was markedly altered compared with control, favoring the N-A isomer (N-B:N-A:N-C:N-D, 01:34:01:02). In addition, aninvestigation of MgCl2 effects on CYP3A4-mediated metabolism of triazolam revealed that 10 mM MgCl2 increased the apparent K-m of triazolam 4-hydroxylation from 83 to 173 mu M and reduced the V-max for the reaction from 3.4 to 2.4 min(-1). Moreover, when the reaction kinetics of the oxidation of pyrene by CYP3A4 was examined in the absence of MgCl2, it was found that the substrate-velocity curve was best approximated by a sigmoidal velocity curve (Hill coefficient 1.7 +/- 0.1). However, when the reaction was conducted in the presence of 10 mM MgCl2, the resulting pyrene kinetics was not sigmoidal but rather biphasic (Hill coefficient 0.80 +/- 0.07). Based on the current results, it appears that CYP3A4 is conformationally sensitive to its in vitro environment and parameters, such as the presence of a divalent magnesium, can have a measurable effect on active site topography and consequently catalytic activity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 22/01/20 alle ore 06:58:39