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Prevalence of CYP2D6 gene duplication and its repercussion on the oxidative phenotype in a white population
Author(s) -
Agúndez José A. G.,
Ledesma María C.,
Ladero José M.,
Benítez Julio
Publication year - 1995
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/0009-9236(95)90151-5
Subject(s) - restriction fragment length polymorphism , genetics , genotype , biology , cyp2d6 , allele , gene , gene duplication , polymorphism (computer science) , population , microbiology and biotechnology , medicine , environmental health
The occurrence of multiple copies of the CYP2D6 gene was investigated in 217 white healthy Spaniards by the combined use of Xba I and Eco RI restriction fragment length polymorphism (RFLP) analyses. About 3.5% of the alleles yielded an 12.1 kb Eco RI‐RFLP product in combination with the 42 kb Xba I‐RFLP product, which is indicative of multiple CYP2D6 . The prevalence of subjects carrying multiple CYP2D6 was 7%. The 12.1 kb Eco RI‐RFLP product was highly associated (60%) with the presence of the genotype 29wt/42wt, as characterized by mutation‐specific polymerase chain reaction and Xba I‐RFLP analyses. Six subjects who had multiple CYP2D6 had other genotypes, namely, 44wt/42wt (four subjects), 29C/42wt (one subject), and one subject had a 12.1 kb product plus the CYP2D6C mutation associated with the 44 kb/42 kb genotype. All subjects identified as carrying multiple CYP2D6 had only two CYP2D6 copies in the same chromosome and were classified as carriers of the (CYP2D6L) 2 allelic variant. Phenotyping with debrisoquin indicated an increase in the oxidative capacity as a function of the number of functional CYP2D6 genes. The metabolic ratio and the 95% confidence limits were as follows: subjects lacking functional genes, 48.8 (95% confidence limits, 14.4 to 79.3); subjects with one functional gene, 2.14 (95% confidence limits, 0.61 to 3.67); subjects with two functional genes, 1.5 (95% confidence limits, 0.88 to 2.14); and subjects with three functional genes, 0.33 (95% confidence limits, 0.22 to 0.45). Our findings indicate that the prevalence of subjects who are carriers of (CYP2D6L) 2 is at least as frequent as the prevalence of poor metabolizers in the population studied. This may have clinical relevance because the duplicated CYP2D6 gene encodes an active enzyme, and its presence significantly ( p < 0.002) accelerates the oxidative metabolism in the population studied. Clinical Pharmacology & Therapeutics (1995) 57 , 265–269; doi: