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Titolo:
Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population
Autore:
Griese, EU; Asante-Poku, S; Ofori-Adjei, D; Mikus, G; Eichelbaum, M;
Indirizzi:
Dr Margarete Fischer Bosch Inst Clin Pharmacol, D-70376 Stuttgart, GermanyDr Margarete Fischer Bosch Inst Clin Pharmacol Stuttgart Germany D-70376 Univ Tubingen, Inst Pharmacol, Dept Clin Pharmacol, Tubingen, Germany UnivTubingen Tubingen Germany , Dept Clin Pharmacol, Tubingen, Germany Univ Ghana, Sch Med, Dept Biochem, Accra, Ghana Univ Ghana Accra GhanaUniv Ghana, Sch Med, Dept Biochem, Accra, Ghana Univ Ghana, Sch Med, Ctr Trop Clin Pharmacol & Therapeut, Accra, Ghana Univ Ghana Accra Ghana tr Trop Clin Pharmacol & Therapeut, Accra, Ghana
Titolo Testata:
PHARMACOGENETICS
fascicolo: 6, volume: 9, anno: 1999,
pagine: 715 - 723
SICI:
0960-314X(199912)9:6<715:AOTCGM>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPARTEINE OXIDATION; DEBRISOQUINE; METABOLISM; GHANAIANS; ALLELES; AMPLIFICATION; POLYMORPHISM; DISSOCIATION; GENOTYPE;
Keywords:
CYP2D6; alleles; function; Ghanaians;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
26
Recensione:
Indirizzi per estratti:
Indirizzo: Griese, EU Dr Margarete Fischer Bosch Inst Clin Pharmacol, Auerbachstr 112, D-70376 Stuttgart, Germany Dr Margarete Fischer Bosch Inst Clin PharmacolAuerbachstr 112 Stuttgart Germany D-70376
Citazione:
E.U. Griese et al., "Analysis of the CYP2D6 gene mutations and their consequences for enzyme function in a West African population", PHARMACOGEN, 9(6), 1999, pp. 715-723

Abstract

The data on differences in the metabolic handling of the CYP2D6 probe drugs sparteine and debrisoquine, and the relationship between phenotype and genotype and gene frequencies for several mutant CYP2D6 alleles in African populations are limited and sometimes controversial. Therefore, in a West African population (Ghana), we investigated (i) the phenotype for sparteine (n= 326) and debrisoquine (n = 201) oxidation, (ii) the coregulatory controlof sparteine and debrisoquine by phenotyping 201 individuals with both drugs and (iii) the genotype for CYP2D6 alleles *3 and *4 in 133 individuals and for the alleles *1, *2, *3, *4, *5, *6, *7, *8, *9, *10, *14, *16, *17, *2b, *2xN, *2bxN in 193 individuals. Of the 326 individuals phenotyped withsparteine, eight had a metabolic ratio (MR)(sp) > 20 corresponding to a poor metabolizer frequency of 2.5% [95% (confidence interval) CI = 1.06-4.77]. The prevalence of the poor metabolizer phenotype for debrisoquine oxidation was 3% (95% CI = 1.1-6.39) with six of the 201 individuals having a MR greater than 12.6. The distribution of the MR of sparteine was trimodal whereas MR of debrisoquine was unimodally distributed with a pronounced kurtosis. In individuals phenotyped with both drugs, there was a significant correlation between the MRs (r(s) = 0.63, P < 0.001). The CYP2D6 alleles *1, *2 and *17 were the most common functional alleles occurring with frequencies of 43.7, 10.6 and 27.7%, respectively. The three other observed functional alleles *2xN, *10 and *20 had much lower frequencies (1.6%, 3.1% and 0.3%, respectively). Of the eight non-functional alleles, only *4 (6.3%) and *5 (6.0%) could be found. The allele *5 occurred with the same frequency as in Caucasian populations (4.1%) but the *4 allele had a much lower frequency (Caucasians 19.5%). One individual with *1/*1 was a poor metabolizer for sparteine and debrisoquine indicating the existence of as yet unknown non-functional alleles in this West African population. Although the prevalence of poor metabolizers and the number of heterozygotes for non-functional alleles was much lower in Ghanaians, the median MRsp of 0.7 was significantly higher in this population compared with a median MRsp of 0.4 in Caucasians, indicating a lower metabolic clearance for CYP2D6 substrates in the West Africans. The lower metabolic activity in Ghanaians could not be explained solely by the high frequency of the *17 allele, which is associated with an impairment of CYP2D6 enzyme function. In addition, a higher median MRsp of 0.5corresponding to metabolic clearance of 346 ml/min was observed among extensive metabolizers with the genotype *1/*1. Thus, compared with the median of MRsp = 0.28 (CLmet 573 ml/min) in Caucasians homozygous for *1, the metabolic clearance of sparteine was 40% lower on average in respective Ghanaians. Pharmacogenetics 9:715-723 (C) 1999 Lippincott Williams & Wilkins.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/01/20 alle ore 13:16:09