Genetic polymorphisms and CYP2D6 activity in Thai subjects

Abstract

CYP2D6 plays a major role in the metabolism of many clinically used drugs and is known to be genetically polymorphic resulting in a high degree of interindividual variation in drug therapy. Eight of CYP2D6 alleles have been characterized and six of them were found in Thai subjects. The genotype results are generally in agreement with those found in other Asians but different from those of Caucasians. CYP2D6*10 has the highest frequency (69.49%) with *10A being less frequent than *10B. The high prevalence of CYP2D6*10 results in a lower frequency of CYP2D6*2 (1.69%). CYP2D6*4 and *5 are found slightly more frequent than those found in other Asian population. Homozygous of CYP2D6*5 which is rare in Asians was unexpectedly detected in 2 individuals out of 7 mutants. Al subjects constantly exhibits C2938 -->T together with CYP2D6*1, *4, and *10 alleles which possibly are the unique characteristic of CYP2D6 alleles in Thais that have an additional C2938 -->T change different from the proposed alleles. CYP2D6 activity was measured from the dextromethorphan O-demethylation reaction using HPLC for the detection of metabolite. Each genotype was compared with corresponding phenotype and the correlation was shown. EM/EM group has significantly (p<0.05) higher enzyme activity when compared to IM/PM and PM/PM group. Extensive metabolizer (EM) presents higher V[subscript max] and lower apparent K[subscript m] than those of intermediate metabolizers (IM). Two individuals with PM/PM were found with a remarkably low enzyme activity. This study represents the first genotype-phenotype correlation study of CYP2D6 in Thailand.