Polymorphic Cytochrome P450 2D6: Humanized Mouse Model and Endogenous Substrates

Abstract

Cytochrome P450 2D6 (CYP2D6) is the first well‐characterized polymorphic phase I drug‐metabolizing enzyme, and more than 80 allelic variants have been identified for the CYP2D6 gene, located on human chromosome 22q13.1. Human debrisoquine and sparteine metabolism is subdivided into two principal phenotypes—extensive metabolizer and poor metabolizer—that arise from variant CYP2D6 genotypes. It has been estimated that CYP2D6 is involved in the metabolism and disposition of more than 20% of prescribed drugs, and most of them act in the central nervous system or on the heart. These drug substrates are characterized as organic bases containing one nitrogen atom with a distance about 5, 7, or 10 Å from the oxidation site. Aspartic acid 301 and glutamic acid 216 were determined as the key acidic residues for substrate‐enzyme binding through electrostatic interactions. CYP2D6 transgenic mice, generated using a lambda phage clone containing the complete wild‐type CYP2D6 gene, exhibits enhanced metabolism and disposition of debrisoquine. This transgenic mouse line and its wild‐type control are models for human extensive metabolizers and poor metabolizers, respectively, and would have broad application in the study of CYP2D6 polymorphism in drug discovery and development, and in clinical practice toward individualized drug therapy. Endogenous 5‐methoxyindolethylamines derived from 5‐hydroxytryptamine were identified as high‐affinity substrates of CYP2D6 that catalyzes their O‐demethylations with high enzymatic capacity and specificity. Thus, polymorphic CYP2D6 may play an important role in the interconversions of these psychoactive tryptamines, including a crucial step in a serotonin‐melatonin cycle.