CYP2D6 polymorphism and its clinical implications

Abstract

Abstract. CYP2D6 is the most important enzyme in the metabolism of drugs and is responsible for the metabolism of 25% of all drugs currently available on the market. CYP2D6 is not only expressed in liver but also in gut and brain neurons, where endogenous substrates with high turnover have been found. Expression of CYP2D6 is not regulated by any known environmental agents and is not inducible by known hormones, in contrast to other hepatic xenobiotic metabolizing cytochrome P450s. CYP2D6 activity is inherited as a monogenetic trait, and the CYP2D6 gene appears to be highly polymorphic in humans. The polymorphic alleles may lead to altered activity of the CYP2D6 enzyme causing absent, decreased, or increased metabolism that in turn influences the disposition of about 50% of metabolized drugs. Currently, more than 63 different functional CYP2D6 gene variants have been described. Among them, the most important variants are CYP2D6*4 (splice defect) and CYP2D6*5 (gene deletion), whereas the common alleles with severely reduced activity are CYP2D6*10, CYP2D6*17, and CYP2D6*41 (splicing defect). CYP2D6*17 decreases CYP2D6 activity in a substrate-dependent fashion, howeverthis has not been shown for other variants. The CYP2D6 gene is subject to many copy number variants. These gene duplication events include functional, partly functional, and nonfunctional genes. Duplication or multiplications of active CYP2D6 genes results in ultra-rapid enzyme activity. The CYP2D6 alleles are subject to very important interethnic differences. The poor metabolizer phenotype (PM) is mainly found in Europe and the ultrarapid metabolizer phenotype (UM) in North Africa and Oceania, whereas the intermediate metabolizer phenotype is mostly located in Asia, due to the high prevalence of the CYP2D6*10 allele. Therefore, for clinical trials and drug therapy, the allelic constitution of a given patient is an important aspect to consider with respect to proper dosing and registering a genotype-phenotype. In the past, the PM phenotype has been much discussed in relation to adverse reactions. However, the UM phenotype has also been associated with adverse drug reactions, mainly as a result of high levels of drug metabolites. The CYP2D6 polymorphism appears to be the most clinically relevant of all presently known polymorphic genes with respect to drug therapy.