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 A 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-methoxyindole- thylamines 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.

Cytochrome P450–mediated drug metabolism in the brain

“…[71][72][73][74] These enzymes are expressed in the brain, and they can all metabolize endogenous neural substrates, suggesting that these genotype-phenotypepersonality associations may be manifested, at least in part, through altered brain metabolism of CNS neurochemicals. CYP2D6 can participate in the metabolism of neurochemicals that influence psychological state, such as the formation of the catecholamines dopamine from tyramine 62,63,75 and serotonin from 5-methoxytryptamine 76,77 and the metabolism of the endogenous cannabinoid anandamide 78 and the neurosteroid progesterone.…”

Cytochrome P450 and Xenobiotic Receptor Humanized Mice

“…CYP2D6 is involved in the metabolism of a large number of clinically used drugs (30,70) (Table 1); it does not produce any electrophilic metabolites that would cause toxicity or cancer. Two pseudogenes, designated CYP2D7P and CYP2D8P, are also found in humans.…”

Pharmacokinetic Interactions between Monoamine Oxidase A Inhibitor Harmaline and 5-Methoxy-N,N-Dimethyltryptamine, and the Impact of CYP2D6 Status

“…In this study, we aimed to delineate the PK interactions between harmaline and 5-MeO-DMT at multiple dose levels including nontoxic and toxic dose combinations in wild-type and Tg-CYP2D6 mouse models that mimic human CYP2D6 poor and extensive metabolizers, respectively (Corchero et al, 2001;Yu et al, 2004). Both blood and brain 5-MeO-DMT and bufotenine concentrations were measured to determine the impact of harmaline on PK of 5-MeO-DMT and metabolite bufotenine as well as the influence of CYP2D6 status.…”