Frequenci es of CYP2D6 mutant alleles in a normal Japanese population and metabolic activity

In this study, we determined the frequencies of CYP2D6 mutant alleles in 162 normal Japanese subjects and 37 human liver microsomes using PCR methods. Moreover, we examined the metabolic activity for bufuralol (BL) 1'-hydroxylation, desipramine (DMI) 2-hydroxylation and dextromethorphan (DM) O-demethylation using 37 human liver microsomes genotyped. The results showd that the most frequentry occurring mutant allele in our Japanese subject was CYP2D6*10, followed by *2, *5 and *14 with frequencies of 38.6 %, 13.0%, 6.2% and 2.2 %, respectively. The frequencies of CYP2D6 mutant alleles in 37 human liver microsomes were consistent with that of normal Japanese subjects. In vitro study, human liver microsomes with CYP2D6*10/*10 genotypes showed the catalitic activity of one third of the *1/*1 genotypes for BL F-hydroxylation, DMI 2-hydroxylation and DM 0demethylation. Among 37 human liver microsomes studied, only one CYP2D6*5 homozygote (*51*5) was identified. The mean metabolic ratio of human liver microsomes with CYP2D6*51*5 genotype predicting poor metabolizer (PM) showed lowest activity in 37 subjects. The CYP2D6 protein contents in human liver microsomes with CYP2D6*5l*10 and *10l*10 genotypes showed half of the *1/*1 genotypes using immunoassay, whereas CYP2D6 mRNA with*10/*10 genotypes was 2.2-fold higher than that of the *1/*1 genotypes (p < 0.05). Therefore, the difference between CYP2D6*10/*10 and *1/*1 genotypes in catalytic activity appear to be explained by the instability of *10 protein. In conclusion, the most frequent mutant alleles of CYP2D6 in Japanese subjects is CYP2D6*10, which is associated with a decreased activity for BL 1'-hydroxylation, DMI 2-hydroxylation and DM O-demethylation. In addition, CYP2D6*5 and *14 are the major mutant alleles responsible for 83 % of the PM phenotypes in Japanese subjects.