No abstract

The occurrence of multiple copies of the CYP2D6 gene was investigated 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).(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

The debrisoquin hydroxylation polymorphism is an autosomic recessive trait of the cytochrome P450IID6, an enzyme involved in drug metabolism, that affects 5% to 10% of white subjects. The genetic basis of this polymorphism was studied in 258 unrelated Spanish white subjects. The results revealed that about 5% of the subjects were homozygous for mutant alleles and that about 1% of the subjects carried alleles that suggested CYP2D6 gene duplication. The extensive metabolizers who were homozygous for the wild-type allele had higher metabolic ratio than the heterozygous extensive metabolizers, indicating a gene-dose effect for the wild type allele. The CYP2D6 allele frequencies indicate a reduced frequency for the CYP2D6(B) allele and a higher frequency for the wild-type allele compared with other white populations. This is also reflected in an increased frequency of the subjects who were homozygous for the wild-type allele among extensive metabolizers. We conclude that the same CYP2D6 mutations are present in Spaniards and other white subjects. Nevertheless, the frequencies of such mutations are different in our population. This implies that a high number of Spanish subjects may behave differently than other white subjects in the effect of drugs metabolized by the CYP2D6 enzyme.