GENETIC-BASIS FOR A LOWER PREVALENCE OF DEFICIENT CYP2D6 OXIDATIVE DRUG-METABOLISM PHENOTYPES IN BLACK-AMERICANS

被引:100
作者
EVANS, WE
RELLING, MV
RAHMAN, A
MCLEOD, HL
SCOTT, EP
LIN, JS
机构
[1] ST JUDE CHILDRENS RES HOSP, DEPT BIOSTAT, MEMPHIS, TN 38101 USA
[2] UNIV TENNESSEE, CTR PEDIAT PHARMACOKINET & THERAPEUT, DEPT PEDIAT, MEMPHIS, TN 38101 USA
[3] UNIV TENNESSEE, DEPT CLIN PHARM, MEMPHIS, TN 38101 USA
关键词
CYP2D6; PHARMACOGENETICS; ETHNIC DIFFERENCES; OXIDATIVE METABOLISM;
D O I
10.1172/JCI116441
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Debrisoquin hydroxylase (CYP2D6) is a cytochrome P450 enzyme that catalyzes the metabolism of > 30 commonly prescribed medications. Deficiency in CYP2D6 activity, inherited as an autosomal recessive trait, was found to be significantly less common in American blacks (1.9%) than whites (7.7%). To determine the genetic basis for this difference, inactivating CYP2D6 mutations were assessed by allele-specific PCR amplification and RFLP analyses of genomic DNA from 126 unrelated whites and 127 unrelated blacks. Blacks had a twofold lower frequency (8.5 versus 23%, P = < 0.001) of the CYP2D6(B) mutation (point mutation at intron 3/exon 4 splice site), while complete deletion of the CYP2D6 gene (5.5% blacks, 2.4% whites), and the CYP2D6(A) mutation (single nucleotide deletion in exon 5; 0.24% blacks, 1.4% whites) were not different between the two groups. The prevalence of heterozygous genotypes was significantly lower in blacks (25 versus 42% of extensive metabolizers, P = 0.009), consistent with the observed prevalence of the deficient trait in blacks and whites. We conclude that the same CYP2D6 mutations lead to a loss of functional expression in blacks and whites, but American blacks have a lower prevalence of the deficient trait due to a lower frequency of the CYP2D6(B) mutation. This could explain racial differences in drug effects and disease risk.
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收藏
页码:2150 / 2154
页数:5
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