Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity

CYP2D6 is of great importance for the metabolism of clinically used drugs and about 20 - 25% of those are metabolised by this enzyme. In addition, the enzyme utilises hydroxytryptamines as endogenous substrates. The polymorphism of the enzyme results in poor, intermediate, efficient or ultrarapid metabolisers ( UMs) of CYP2D6 drugs. It is plausible that the UM genotype, where more than one active gene on one allele occurs, is the outcome of selective dietary selection in certain populations in North East Africa. The UM phenotype affects 5.5% of the population in Western Europe. A hypothesis for the evolutionary basis behind selection for CYP2D6 gene duplications is presented in relation to selection for Cyp6 variants in insecticide resistant Drosophila strains. The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use, which are CYP2D6 substrates. The consequences of the polymorphism at ordinary drug doses can be either adverse drug reactions or no drug response. Examples are presented where CYP2D6 polymorphism affects the efficacy and costs of drug treatment. Predictive CYP2D6 genotyping is estimated by the author to be beneficial for treatment of about 30 - 40% of CYP2D6 drug substrates, that is, for about 7 - 10% of all drugs clinically used, although prospective clinical studies are necessary to evaluate the exact benefit of drug selection and dosage based on the CYP2D6 genotype.