Cytochrome P450 2D6

Abstract

The cytochrome P450 2D6 (CYP2D6) is an enzyme of great historical importance for pharmacogenetics and is now thought to be involved in the metabolism of up to 25% of the drugs that are in common use in the clinic [1]. Several years before the gene was cloned, researchers observed that Caucasian population responded in a bimodal pattern to certain drugs such as debrisoquine and sparteine [2,3], with most patients exhibiting ‘normal’ pharmacokinetics, whereas others seemed to have great difficulty in metabolizing debrisoquine or sparteine. Debrisoquine and sparteine became examples of so-called probe drugs, and were used to phenotype patients [4]. This finding led researchers to conclude that there were common polymorphisms in an as yet unidentified metabolic gene that contributed to the variable pharmacokinetics of these drugs. The protein responsible for the altered metabolism was later purified from human liver microsomes by Distlerath et al. [5]. The gene encoding this protein was initially localized to chromosome 22 by Eichelbaum et al. [6]. The cDNA was cloned by Gonzalez et al. [7,8] from human liver cDNA libraries using an antibody against the rat ortholog. The deduced human protein revealed 73% sequence similarity with the rat protein and by the use of human–rodent somatic cell hybrids the gene was localized to human chromosome 22 [8], confirming the earlier study [6]. This gene came to be called CYP2D6, and is part of the cytochrome P450 gene family – a group of enzymes that is responsible for phase I metabolism and elimination of numerous endogenous substrates and a diverse array of drugs. Among the drug-metabolizing cytochrome P450s, CYP2D6 is the only noninducible enzyme, which results in a large contribution of genetic variation to the interindividual variation in enzyme activity [1]. CYP2D6 is highly polymorphic, with over 90 known allelic variants [9]. A selection of these variants and haplotypes is described in this summary, and the full list of all named alleles can be found at: http://www.cypalleles.ki.se/cyp2d6.htm.