CYP2D6 polymorphism and its clinical implications

Abstract

CY P2D6 is the most important enzyme in the metabolism ofdrugsandisresponsibleforthe metabolism of25% of all drugs currently available on the market. CYP 2D6 is not only expressed in liver but also in gut and brain neurons, where endogenous substrates with high turnover have been found. Expression of CYP 2D6 is not regul ated by any known environmental agents and is not inducible by known hormones, in contrast to other hepatic xenobiotic metabolizing cytochrome P450s. CYP 2D6 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, CYP2 D6* 17, and CYP2D6*4 1 (splicing defect). CYP2D6*17 decreases CYP2D6 activity in a substrate-dependent fashio n, however