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

Abstract

Aims To determine the molecular basis of the intermediate extensive metaboliser (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 collecting 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 intermediate EM phenotype having lower frequency of CYP2D6 PM alleles. To clarify this discrepancy phenotype-genotype relationship was studied. We found that the CYP2D6*17 and CYP2D6*2 alleles, prevalent in this black population, are characterised by their low capacity for dextromethorphan demethylation. Our data also show that the CYP2D6*1 allele is associated with the highest in vivo activity followed by the CYP2D6*2 allele and then the CYP2D6*17 allele. Conclusions The higher frequencies of the CYP2D6*2 and CYP2D6*17 alleles than the CYP2D6*1 allele account for the high frequency of the intermediate EM phenotype in this black population. The polymorphism of the CYP2D6 enzyme activity in African populations could have important implications for use of drugs that are substrates for CYP2D6 and have a narrow therapeutic window.

Influence of hydroxychloroquine on the bioavailability of oral metoprolol

“…This may indicate that DM‐MR is not a very sensitive marker for inhibition of CYP2D6 and is influenced only when there is a dramatic reduction in the total functional capacity of this enzyme. The results also show that HCQ, and perhaps chloroquine, may be able to change the phenotype of heterozygous EM subjects, and that the phenotypic distribution would be altered by these drugs in populations where the prevalence of mutant alleles is high [36]. The inhibitory effects of HCQ on the CYP2D6‐dependent metabolism of DM and other drugs may be even more pronounced when HCQ is used chronically, as for the treatment of rheumatoid arthritis.…”

In Silieo Study on the Inhibitory Interaction of Drugs with Wild-type CYP2D6.1 and the Natural Variant CYP2D6.17

“…CYP2D6.17 is normally expressed and common in African populations, and has three amino acid substitutions, T107I, R296C, and S486T. 3,9) The frequency of CYP2D6.17 in different African countries is Zimbabwe, 34% 10) ; Ethiopia 9% 11) ; Tanzania, 18% 12) ; Gabon, 24% 13) ; and Ghana, 28%. 14) CYP2D6.…”

Priority pharmacogenetics for the African continent: focus on CYP450

“…These duplications are less frequent in populations of Bantu/Niger-Congo origin, such as the Yoruba in Nigeria (4%), Gabonese (4%) and Ghanaians (1.6%) [49,64,65]. The notion that CYP2D6*2xN is an Afro-Asiatic specific allele is further supported by the fact that these alleles also occur commonly in Saudi-Arabia (20%), and to a lesser extent in African-Americans, Europeans and Asians (<2.5%) [41,66,67].…”