Genetic basis for a lower prevalence of deficient CYP2D6 oxidative drug metabolism phenotypes in black Americans.

Abstract

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. (J. Clin. Invest. 1993. 91:2150-2154

High-throughput analysis of informative CYP2D6 compound haplotypes

“…When combined with previously published methods to detect CYP2D6*5 alleles (that are not compatible with multiplexing), this approach can identify ϳ90% of individuals in Western European populations with PM phenotype [39]. CYP2D6*4 is also found at relatively high frequencies in several non-European populations: 8.3% in Canadian Inuit [40], 8.5% in African Americans [41], and 11.3% in Turks [42]. Due to the low incidence of defective alleles in Africans and Oriental Asians, PM phenotypes are rare in these populations compared with Western Europeans [43].…”

Therapeutic Drug Monitoring of Nortriptyline in Smoking Cessation: A Multistudy Analysis

“…Ziegler et al, (1977) observed that nortriptyline concentrations were nearly 50% higher in African-Americans than Whites (113.5 vs.75.7 ng/mL). The potential genetic basis for ethnic differences in PNCs likely relates to differences in the frequency of defective CPY2D6 alleles (i.e., so-called "poor metabolizers"), with a higher rate of defective alleles for this enzyme generally, but not always, observed in Asians and those of African ancestry [30][31][32][33][34][35]. For a given dose of nortriptyline, higher plasma concentrations of the drug will be achieved due to slower metabolism.…”

Development and validation of simple, rapid and sensitive LC-PDA ultraviolet method for quantification of Nebivolol in rat plasma and its application to pharmacokinetic studies

“…The metabolism by aromatic hydroxylation in humans is subject to the CYP2D6-dependent genetic oxidative polymorphism [6]. The patients deficient with CYP2D6 enzyme activity (2% of African-Americans, 2% of Asians, 7% of Caucasians) are considered poor metabolizers of NBL [7][8]. The absolute oral bioavailability of NBL is 12% in extensive metabolizers and 96% in poor metabolizers with the mean terminal half-life of approximately 10 h [9].…”