Characterization of CYP2D6 genotypes and metabolic profiles in the Portuguese population: pharmacogenetic implications.

Abstract

CYP2D6 codes for a protein that is vastly involved in the metabolism of various substances. This gene is highly polymorphic, which influences the enzymatic activity and contributes to the huge variability in the enzyme hydroxylation capacity. Different metabolic profiles determine the processing of xenobiotics and endobiotics, thereby influencing disease risk, therapeutic efficacy and side effects, or toxicity of xenobiotics. The aim of this work was to characterize CYP2D6 polymorphisms and predict metabolic profiles in the Portuguese population. The study comprised 300 Portuguese unrelated healthy adult volunteers. Genetic analysis included allelic discrimination and copy number determination with TaqMan® probes by real-time PCR and allele duplications of CYP2D6*1, CYP2D6*2, CYP2D6*4 and CYP2D6*10 were confirmed by long PCR and PCR-RFLP. The percentages of poor and ultrarapid metabolizers found in this Portuguese population were 6.3 and 4.7%, respectively. Compared with other studies, such as in Spaniards, the allelic frequencies observed were similar, with some exceptions, such as for CYP2D6*10, which is higher in the Portuguese population, and for CYP2D6*6 and duplication of *1 and *2, appearing in lower frequencies in the present study. These results allow the determination of the frequency of the most relevant CYP2D6 polymorphisms and the prediction of the enzyme metabolic activity, being of much importance for the CYP2D6 pharmacogenetics approach in the Portuguese population. The data presented here are significant for the study of genetic variability influencing CYP2D6 activity, to improve the effectiveness and safety of xenobiotics exposure, also can be used as a tool in clinical practice for the development of individualized pharmacotherapy.