ABSTRACT
CYP2D6 metabolizes ~25% of clinical drugs in the human liver (Cascorbi 2003; Gardiner and Begg 2006; Ingelman-Sundberg 2005; Ingelman-Sundberg et al. 2007; Zhou et al. 2009). Phenotypically, the CYP2D6 ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs), and poor metabolizers (PMs) compose approximately 3%–5%, 70%–80%, 10%–17%, and 3%–7% of the Caucasian population, respectively (Sachse et al. 1997). There is a large interindividual variation in the enzyme activity of CYP2D6. The CYP2D6 gene codes for a protein with 497 amino acids (Eichelbaum et al. 1987; Gough et al. 1993; Heim and Meyer 1990; Kimura et al. 1989). CYP2D6 belongs to a gene cluster of highly homologous inactive pseudogenes CYP2D7P and 2D8P (Heim and Meyer 1992; Kimura et al. 1989; Steen et al. 1995). CYP2D6 is also expressed in human kidney (Nishimura et al. 2003), intestine (Madani et al. 1999; Nishimura et al. 2003; Prueksaritanont et al. 1995), breast (Huang et al. 1997), lung (Bernauer et al. 2006; Guidice et al. 1997), placenta (Hakkola et al. 1996), and brain (Chinta et al. 2002; Miksys et al. 2002; Siegle et al. 2001) at low levels. In the resolved crystal structure of human CYP2D6 (Protein Data Bank code: 2F9Q) (Rowland et al. 2006), the activesite cavity is bordered by the heme and lined by residues I1e106, Leu110, Phe112, Phe120, Leu121, G1n117, G1y118, Va1119, A1a122, Leu213, G1u216, Ser217, Leu220, G1n244, Phe247, Leu248, I1e297, A1a300, Asp301, Ser304, A1a305, Va1308, Thr309, Va1370, Met374, G1y373, Phe483, and Leu484. The 2D6 structure has a well-defined active-site cavity above the heme group with a volume of ~540 Å3, which can readily accommodate a number of substrates with distinct structures. This chapter will highlight our current knowledge on the substrate specificity of human CYP2D6.
