CYP2D6 polymorphism in a Gabonese population: contribution of the CYP2D6*2and CYP2D6*17 alleles to the high prevalence of the intermediate metabolicphenotype

Aims To determine the molecular basis of the intermediate extensive metabol iser (EM) CYP2D6 phenotype in healthy Gabonese subjects. Methods The CYP2D6 phenotype of 154 healthy Gabonese subjects was assessed by giving the subject a single dose of 30 mg dextromethorphan, and collecti ng their urine for the next 8 h. The CYP2D6 genotype was determined for 50 individuals of the EM phenotypic group by Southern blotting and various PCR -based procedures aimed at identifying different CYP2D6 alleles. Results We found that in the studied Gabonese population, as compared with a French population, there is significantly higher frequency of intermediat e EM phenotype having lower frequency of CYP2D6 PM alleles. To clarify this discrepancy phonotype-genotype relationship was studied. We found that the CYP2D6(star)17 and CYP2D6(star)2 alleles, prevalent in this black populati on, are characterised by their low capacity for dextromethorphan demethylat ion. Our data also show that the CYP2D6(star)1 allele is associated with th e highest in vivo activity followed by the CYP2D6(star)2 allele and then th e CYP2D6(star)17 allele. Conclusions The higher frequencies of the CYP2D6(star)2 and CYP2D6(star)17 alleles than the CYP2D6(star)1 allele account for the high frequency of the intermediate EM phenotype in this black population. The polymorphism of th e CYP2D6 enzyme activity in African populations could have important implic ations for use of drugs that are substrates for CYP2D6 and have a narrow th erapeutic window.