CYP2D6-RELATED OXIDATION POLYMORPHISM IN A CANADIAN INUIT POPULATION

The xenobiotic oxidation polymorphism associated with cytochrome P450 2D6 (CYP2D6) was investigated in 152 genetically related and unrelated healthy Inuit subjects living in the High Arctic of eastern Canada. P henotyping was based on HPLC determination of the CYP2D6-related dextr omethorphan metabolic ratio in overnight urine samples after oral admi nistration of 30 mg dextromethorphan hydrobromide. The log metabolic r atio was bimodally distributed, with three subjects classified as poor metabolizers (PMs). In subjects unrelated in the first degree, the in cidence of the PM phenotype was 3 of 90 or 3.3%. PCR-based analyses of DNA for variants of the CYP2D6 gene demonstrated that the PMs of dext romethorphan had the defective allele CYP2D64. The estimated frequenc y of the CYP2D64 allele was 0.067-0.083, which is lower than the freq uency in Caucasians but higher than the frequency in Oriental populati ons. The CYP2D63 and the CYP2D6*6 alleles were not detected in the In uit population. The CYP2D610 allele was present in only four unrelate d subjects, classified as extensive metabolizers (EMs), resulting in a n estimated allele frequency of 0.022, which is much lower than in Ori ental populations. This study demonstrated the existence of the CYP2D6 polymorphism in Canadian Inuit, while the frequencies of allelic vari ants of CYP2D6 point to the uniqueness of this population. Several imp ortant therapeutic drugs that are being prescribed in Arctic communiti es will have altered pharmacokinetics in PMs of CYP2D6.