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Titolo:
Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans
Autore:
Dickmann, LJ; Rettie, AE; Kneller, MB; Kim, RB; Wood, AJJ; Stein, CM; Wilkinson, GR; Schwarz, UI;
Indirizzi:
Vanderbilt Univ, Sch Med, Dept Med, Div Clin Pharmacol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Pharmacol, Nashville, TN 37232 USA Univ Washington, Dept Med Chem, Seattle, WA 98195 USA Univ Washington Seattle WA USA 98195 Dept Med Chem, Seattle, WA 98195 USA Vanderbilt Univ, Sch Med, Dept Pharmacol, Div Clin Pharmacol, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Pharmacol, Nashville, TN 37232 USA
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 2, volume: 60, anno: 2001,
pagine: 382 - 387
SICI:
0026-895X(200108)60:2<382:IAFCOA>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
CYTOCHROME-P450 CYP2C9; GENETIC-ANALYSIS; ALLELIC VARIANT; AMINO-ACID; WILD-TYPE; POLYMORPHISM; WARFARIN; ASSOCIATION; METABOLISM; PHENYTOIN;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Kim, RB Vanderbilt Univ, Sch Med, Dept Med, Div Clin Pharmacol, 572 MRB-1,Nashville, TN 37232 USA Vanderbilt Univ 572 MRB-1 Nashville TN USA 37232 lle, TN 37232 USA
Citazione:
L.J. Dickmann et al., "Identification and functional characterization of a new CYP2C9 variant (CYP2C9*5) expressed among African Americans", MOLEC PHARM, 60(2), 2001, pp. 382-387

Abstract

CYP2C9 is a polymorphic gene for which there are four known allelic variants; CYP2C9*1, CYP2C9*2, CYP2C9*3, and CYP2C9*4. In the present study, DNA from 140 European Americans and 120 African Americans was examined by single-strand conformational polymorphism and restriction fragment length polymorphism analyses, resulting in the identification of a new CYP2C9 variant, CYP2C9*5. This variant is derived from a C1080G transversion in exon 7 of CYP2C9 that leads to an Asp360Glu substitution in the encoded protein. The CYP2C9*5 variant was found to be expressed only in African Americans, such that approximately 3% of this population carries the CYP2C9*5 allele. The variant expressed in, and purified from, insect cells infected with a recombinant baculovirus. Comparative kinetic studies using the purified wild-type protein CYP2C9*1; the IIe359Leu variant, CYP2C9*3; and the Asp 360Glu variantCYP2C9*5 were carried out using (S)-warfarin, diclofenac, and lauric acid as substrates. The major effect of the Asp360Glu mutation was to increase the K-m value relative to that of CYP2C9*1 for all three substrates: 12-foldhigher for (S)-warfarin 7-hydroxlation, 5-fold higher for the 4'-hydroxylation of ldiclofnac and 3-fold higher for the omega -1 hydroxlation of lauric acid, V-max values differed less that K-m values between the CYp2C9*1 andCYP2C9*5 proteins. In vitro intrinsic clearances for CYP2C9*5 calculated as the ratio of V-max/K-m, ranged fro 8 to 18% of CYP2C9*1 values. The corresponding ratio for CYP2C9*3 was 4 to 13%. Accordingly, the in vitro data suggest that carriers of the CYP2C9*5 allele would eliminate CYP2C9 substrates at slower rates relative to person expressing the wild-type protein.

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Documento generato il 02/04/20 alle ore 02:47:18