Title: Common mutant alleles of <i>CYP2D6</i> causing the defect of CYP2D6 enzyme activity in a Japanese population
Abstract: CYPD2D6, an isoform of cytochrome P450 catalysing more than 50 clinically important drugs, is highly polymorphic. There are important interethnic differences in the frequencies of poor metabolizers (PM). In our previous study, we reported the frequencies of seven mutated alleles, CYP2D6*1x2, *2, *2x2, *5, *10, *10x2 and *14 in 162 Japanese subjects [1, 2]. Based on the results of that study, the frequency of CYP2D6 PM in the Japanese population was estimated to be 0.71% (95% confidence interval (CI) 0.56, 0.89). However, this frequency is not consistent with the frequency of this PM estimated to be 0.84% (95% CI 0.68, 1.04) by in vivo studies, suggesting that other mutations exist in the CYP2D6 gene in the Japanese population [3]. Recently, it has been reported that CYP2D6*21, in which one nucleotide (2573C) in exon 5 has been inserted, was responsible for the CYP2D6 PM in the Japanese [4]. Furthermore, an individual heterozygous for CYP2D6*36 has been reported to have a metabolic ratio that was just below the antimode for debrisoquine [5]. There is a possibility that CYP2D6*21 or *36 may be included in our Japanese subjects. Therefore, we carried out additional analysis for the frequencies of CYP2D6*21 and *36 variants in the 162 Japanese subjects. Unrelated healthy Japanese (n = 162; 95 males and 67 females) were recruited for the genotyping study. All procedures were approved by the local Institutional Review Board, and all participants provided informed consent [1]. Genotyping for the CYP2D6*21 allele was performed by allele-specific polymerase chain reaction (PCR) as described by Chida et al. [4]. In order to detect CYP2D6*36, assays for the mutations 100C/T and 4180G/C were performed by PCR-restriction fragment length polymorphism [1], and gene conversion in exon 9 derived from CYP2D7 was confirmed by DNA sequencing [6]. In the present study, we detected CYP2D6*21 (in one subject) and CYP2D6*36 (in three subjects), and their frequencies were 0.3% and 0.9%, respectively (Table 1). To our knowledge, this is the first report on the frequency of CYP2D6*36 in a Japanese population. The 17 different genotypes presented in our subjects (i.e. CYP2D6*1/*1, *1/*2, *1x2/*2, *1/*2x2, *1/*5, *1/*10, *1/*10x2, *1/*14, *1/*36, *2/*5, *2/*10, *2/*14, *5/*10, *5/*21, *10/*10, *10/*10X2 and*10/*14) and the frequencies of all the genotypes observed in the present study were within the 95% CI estimated by the Hardy–Weinberg equation (data not shown). CYP2D6*4 and *18, which create defective alleles, were found in a genotyping study on a Japanese population, while these two mutated alleles were not detected in our subjects [7]. We reported that the frequencies of CYP2D6*5 and *14 could account for 83% of Japanese PM in our previous study. In the present study, frequency of PM in the Japanese, calculated by the frequencies of CYP2D6*21 and *36 in addition to those of *5 and *14 in our subjects, was estimated to be 0.92% (95% CI 0.75, 1.13). This estimate is similar to those in previous Japanese population phenotyping studies. Therefore, we suggest that it could be possible to predict most of the CYP2D6 PM phenotype by genotyping tests on six common defective mutated alleles, CYP2D6*4, *5, *14, *18, *21 and *36, in the Japanese. Received 24 June 2002, accepted 3 November 2002 Dr T. Kubota, Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, 7-3-1 Hongoh, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: [email protected]