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Titolo:
Identification and functional characterization of eight CYP3A4 protein variants
Autore:
Eiselt, R; Domanski, TL; Zibat, A; Mueller, R; Presecan-Siedel, E; Hustert, E; Zanger, UM; Brockmoller, J; Klenk, HP; Meyer, UA; Khan, KK; He, YA; Halpert, JR; Wojnowski, L;
Indirizzi:
EPIDAUROS Biotechnol AG, D-82347 Bernried, Germany EPIDAUROS Biotechnol AG Bernried Germany D-82347 82347 Bernried, Germany Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA Univ Texas Galveston TX USA 77550 acol & Toxicol, Galveston, TX 77550 USA Dr Margarete Fischer Bosch Inst Clin Pharmacol, Stuttgart, Germany Dr Margarete Fischer Bosch Inst Clin Pharmacol Stuttgart Germany ermany Humboldt Univ, Univ Med Ctr Charite, Inst Clin Pharmacol, Berlin, Germany Humboldt Univ Berlin Germany rite, Inst Clin Pharmacol, Berlin, Germany Univ Basel, Biozentrum, Div Pharmacol Neurobiol, CH-4003 Basel, Switzerland Univ Basel Basel Switzerland CH-4003 urobiol, CH-4003 Basel, Switzerland
Titolo Testata:
PHARMACOGENETICS
fascicolo: 5, volume: 11, anno: 2001,
pagine: 447 - 458
SICI:
0960-314X(200107)11:5<447:IAFCOE>2.0.ZU;2-D
Fonte:
ISI
Lingua:
ENG
Soggetto:
HUMAN CYTOCHROME-P450 3A4; HUMAN-LIVER; NIFEDIPINE OXIDASE; ALLELIC VARIANT; SUBSTRATE-SPECIFICITY; CATALYTIC ACTIVITY; GENETIC VARIANT; SITE; METABOLISM; EXPRESSION;
Keywords:
CYP3A; CYP3A4; protein variant; drug metabolism; steroid metabolism;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
47
Recensione:
Indirizzi per estratti:
Indirizzo: Wojnowski, L EPIDAUROS Biotechnol AG, Neuland 1, D-82347 Bernried, GermanyEPIDAUROS Biotechnol AG Neuland 1 Bernried Germany D-82347 y
Citazione:
R. Eiselt et al., "Identification and functional characterization of eight CYP3A4 protein variants", PHARMACOGEN, 11(5), 2001, pp. 447-458

Abstract

The genetic component of the inter-individual variability in CYP3A4 activity has been estimated to be between 60% and 90%, but the underlying geneticfactors remain largely unknown. A study of 213 Middle and Western EuropeanDNA samples resulted in the identification of 18 new CYP3A4 variants, including eight protein variants, A total of 7.5% of the population studied wasfound to be heterozygous for one of these variants, in a bacterial heterologous expression system, two mutants, R130Q and P416L, did not result in detectable P450 holoprotein. One mutant, T363M, expressed at significantly lower levels than wild-type CYP3A4, G56D, V170I, D174H and M445T were not significantly different when compared with wild-type CYP3A4 in expression or steroid hydroxylase activity, L373F displayed a significantly altered testosterone metabolite profile and a four-fold increase in the K-m value for 1'-OH midazolam formation. The results suggest a limited contribution of CYP3A4 protein variants to the inter-individual variability of CYP3A4 activity in Caucasians, Some variants may, however, play a role in the atypical response to drugs or altered sensitivity to carcinogens. Pharmacogenetics 11:447-458 (C) 2001 Lippincott Williams & Wilkins.

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Documento generato il 18/01/20 alle ore 02:20:56