¹Department of Pharmacology, Medical School, University of Extremadura, Badajoz, and the Gastroenterology Unit, University Hospital San Carlos, University Complutense, Madrid, Spain

Correspondence: Julio Benítez, MD, PhD, Departamento de Farmacología, Facultad de Medicina, Universidad de Extremadura, Avda. de Elvas s/n, 06071, Badajoz, Spain.

^*Supported in part by grants CICYT-SAF92-0333 from Comision Interministerial de Ciencia y Tecnología, Madrid, Spain, and FISss 93/0632 from Fondo de Investigaciones Sanitarias de la Seguridad Social, Madrid, Spain. This work has been done within a European collaborative group of the Center for Cooperation in the field of Scientific and Technical Research (COST) of the European Communities (EC), project B1, phase II (Brussels, Belgium).

Received 25 July 1994; Accepted 21 September 1994.

Abstract

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.