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Titolo:
Characterization of the CYP2D6*29 allele commonly present in a blade Tanzanian population causing reduced catalytic activity
Autore:
Wennerholm, A; Johansson, I; Hidestrand, M; Bertilsson, L; Gustafsson, LL; Ingelman-Sundberg, M;
Indirizzi:
Huddinge Univ Hosp, Karolinska Inst, Dept Med Lab Sci & Technol, Div Clin Pharmacol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 col, S-14186 Huddinge, Sweden Karolinska Inst, IMM, Div Mol Toxicol, Stockholm, Sweden Karolinska Inst Stockholm Sweden MM, Div Mol Toxicol, Stockholm, Sweden
Titolo Testata:
PHARMACOGENETICS
fascicolo: 5, volume: 11, anno: 2001,
pagine: 417 - 427
SICI:
0960-314X(200107)11:5<417:COTCAC>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
KIDNEY CORTEX MICROSOMES; CYP2D6 GENE; YEAST-CELLS; DEBRISOQUINE HYDROXYLATION; MONOOXYGENASE ACTIVITIES; AFRICAN POPULATION; ENZYME FUNCTION; HUMAN-LIVER; AMINO-ACID; CYTOCHROME-P450;
Keywords:
genetic polymorphism; single nucleotide polymorphism; bufuralol; debrisoquine;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Wennerholm, A Huddinge Univ Hosp, Karolinska Inst, Dept Med Lab Sci & Technol, Div Clin Pharmacol, S-14186 Huddinge, Sweden Huddinge Univ Hosp Huddinge Sweden S-14186 uddinge, Sweden
Citazione:
A. Wennerholm et al., "Characterization of the CYP2D6*29 allele commonly present in a blade Tanzanian population causing reduced catalytic activity", PHARMACOGEN, 11(5), 2001, pp. 417-427

Abstract

Debrisoquine metabolism among Tanzanians has been found to be slower than expected from the CYP2D6 genotype. in order to evaluate any genetic explanation, the coding sequence and intron-exon boundaries of the CYP2D6 gene from three Black Tanzanian volunteers with a CYP2D6*/*1 or CYP2D6*2/*2 genotype and debrisoquine metabolic ratios (MRs)>1 were fully sequenced to screen for new mutations. Two functional mutations, G(1747) to A (causing V136I) and G(3271) to A (causing V338M), were identified in the CYP2D6*2/*2 sample. Thirty-six subjects (34%) out of a total 106 subjects were heterozygous and three subjects (3%) were homozygous for the allele, yielding an allele frequency of 20%, The CYP2D6*29 allele, having also the mutations of the CYP2D6*2 allele, was subsequently expressed in yeast and mammalian COS-I cells,No differences were seen with respect to the affinity (K-m) or maximal velocity (V-max) of the CYP2D6 substrate bufuralol between the wild-type and mutant when expression was carried out in yeast cells, By contrast, the 1'-hydroxybufuralol catalytic activity of the mutant expressed in COS-I cells was only 26% of the wild-type (P<0.01; Mann-Whitney U-test) and its debrisoquine hydroxylation activity was 63% of that of CYP2D6.1. The single mutantsV136I and V338M had reduced capacity for bufuralol hydroxylation, but the effect was even stronger when both mutations were present together as in CYP2D6.29. Analysis of the distribution of CYP2D6*29 in subjects phenotyped for debrisoquine revealed that this allele significantly causes a reduction in the rate of debrisoquine hydroxylation in vivo, The results indicate thecommon existence in Tanzanians of a variant CYP2D6 form with different substrate specificity as compared to the wild-type form of the enzyme causing reduced capacity for debrisoquine metabolism, Pharmacogenetics 11:417-427 (C) 2001 Lippincott Williams & Wilkins.

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Documento generato il 02/04/20 alle ore 02:52:29