Genetic Analysis of the CYP2D6 Locus in a Hong Kong Chinese Population (Molecular Diagnostics and Genetics‪)‬

Debrisoquine-4-hydroxylase, a cytochrome P450 enzyme known as CYP2D6 enzyme, metabolizes different types of pharmacotherapeutic drugs, such as tricyclic antidepressants and neuroleptics. The gene encoding for CYP2D6 enzyme, CYP2D6, is part of a cluster on chromosome 22 that includes two to three related pseudogenes (1). Starting at the 5' end of the cluster, there are two nonfunctional pseudogenes, CYP2D8P and CYP2D7AP (an additional pseudogene CYP2D7BP can also be found), followed by the active gene, CYP2D6. Several mutated alleles of the CYP2D6 locus have been identified and associated with alterations in the metabolism of debrisoquine and related drugs. Consequently, the activity of the CYP2D6 enzyme ranges from ultrarapid (ultrarapid me tabolizer) to a complete absence [poor metabolizer (PM)]. [3] Individuals homozygous or heterozygous for deficient CYP2D6 alleles metabolize drugs at lower rates, which leads to an increased risk of side effects and drug toxicity. On the other hand, individuals with duplication of either the active gene CYP2D6 or the CYP2D6*2 allele metabolize drugs at ultrarapid rate, which may lead to therapeutic failure. In addition to interindividual variability in CYP2D6 enzyme activity, the incidence of PMs of debrisoquine has been shown to vary between different populations. The prevalence of PMs ranges from 1% in some Oriental populations to as high as 19% in some black populations (2). In particular, differences between Caucasian and Oriental populations have been studied exhaustively (3-8). Interracial differences are explained by an unequal distribution of the alleles of the CYP2D6 gene among different populations. The defective alleles CYP2D6*3 and CYP2D6*4 that give rise to the PM phenotype in Caucasians are rarely found in Chinese, explaining the low frequency of PMs in this population. However, these two races differ not only in the incidence of PMs but also in the activity of debrisoquine hydroxylase within the extensive metabolizer (EM) phenotype. The distribution of the debrisoquine metabolic ratios is shifted toward higher values among Chinese EMs, indicating lower CYP2D6 enzyme activity. These individuals are classified as intermediate metabolizers. The lower enzyme activity in Oriental EMs is associated with the frequent presence of the allele CYP2D*10 and its variants, CYP2D*10A and CYP2D*10B. These alleles contain a [C.sub.188] [right arrow] T mutation that causes a [Pro.sub.34] [right arrow] Ser amino acid substitution, leading to the formation of an unstable enzyme with lower metabolic activity (3).