ABSTRACT
CYPs are heme-containing enzymes that are responsible for metabolizing numerous endogenous and exogenous compounds, including hydroxytryptamines, steroids, drugs, procarcinogens, neurotoxins, and environmental compounds (Nebert and Dalton 2006; Nebert and Russell 2002; Nebert et al. 2013; Nelson et al. 2013). There are clear differences between humans and other animal species with regard to the tissue distribution, regulation, substrate specificity, and inhibitor selectivity of CYPs (Emoto et al. 2013; Graham and Lake 2008; Marathe and Rodrigues 2006; Martignoni et al. 2006). The human CYP2D6 gene consists of nine exons coding for a coding for a 497–amino acid protein with a molecular weight of 55.8 kDa (Eichelbaum et al. 1987; Heim and Meyer 1990; Kimura et al. 1989). CYP2D6 belongs to a gene cluster containing five highly homologous inactive pseudogenes (Table 2.1) (Heim and Meyer 1992; Kimura et al. 1989; Steen et al. 1995). The CYP2D6 gene is conserved in chimpanzee, rhesus monkey, rat, chicken, and frog. In humans, CYP2D6 is involved in the metabolism of more than 150 drugs and approximately 25% of commonly prescribed drugs, although it only constitutes 2%-4% of the total hepatic CYPs (Zhou et al. 2009). Its substrates include antidepressants, antipsychotics, analgesics and antitussives, β-blocking agents, antiarrhythmics, and antiemetics. Human CYP2D6 is largely not inducible but is subject to inhibition by a large number of drugs and other compounds (Zhou et al. 2009). Classic xenobiotic inducers that transactivate pregnane X receptors, aryl hydrocarbon receptors, and constitutive androstane receptors do not induce CYP2D6. However, the orphan nuclear receptor HNF-4α regulates CYP2D6 transcription via binding to a direct repeat site (DR1) on the CYP2D6 promoter (Cairns et al. 1996). In CYP2D6-humanized mice lacking Hnf-4α in the liver, a 50% decrease in CYP2D6 mRNA and activity is observed (Corchero et al. 2001). However, HNF-4α is a common regulator of many hepatic P450 enzymes, which all change in a different manner during pregnancy, and thus it is unlikely that changes in CYP2D6 activity during human pregnancy can be completely explained by changes in HNF-4α-mediated transcriptional activity. Furthermore, human CYP2D6 is highly polymorphic, which often causes altered or abolished enzyme activities, leading not only to severe adverse effects in pharmacotherapy but also to therapeutic failure (Gaedigk 2013; Haertter 2013; Teh and Bertilsson 2012; Zhou 2009a,b). The genetic variations in CYP2D6 results in four different drug metabolism phenotypes: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). The latter is the result of gene duplication/multiplication and occurs with inheritance of more than two copies of the fully functional CYP2D6 alleles. The crystal structure of human CYP2D6 has been determined and shows the characteristic CYP fold observed for other members of the CYP superfamily (Nguyen and Conley 2008; Rowland et al. 2006; Wang et al. 2012). The lengths and orientations of the individual secondary structural elements in the CYP2D6 structure are similar to those seen in other human CYP2 members, such as CYP2C8 and 2C9. Many important amino acid residues in the active site of human CYP2D6 are implicated in substrate recognition and binding, including Phe120, G1u216, Asp301, Phe481, and Phe483.
