Translation of CYP2D6 Human Genetic Variation into Medical Practice: Lessons Learned and the Way Forward

Marion      Lorenz; Stefan      Prause; Moritz      Eidens; Alexander      Weise; Marco      Klemm; Andreas      Pfutzner; Thomas      Schondorf; Matthias      M. Weber

doi:10.2174/187569210793368249

Abstract

The polymorphic cytochrome P450 2D6 (CYP2D6) enzyme, a member of the cytochrome P450 mixed-function oxidase system, is one of the clinically most important enzymes involved in the metabolism of drugs and other xenobiotics. This highly polymorphic enzyme exhibits vastly different phenotypes: poor metabolizers show no enzyme activity, whilst ultrarapid metabolizers exhibit a significantly higher activity. Between these two extremes, there are the extensive and intermediate metabolizers, two heterogeneous groups with overlapping boundaries concerning CYP2D6 activity. These different phenotype groups can be correlated partly to the genotype of an individual. More than 70 different CYP2D6 alleles have been described to date, which encode for null alleles, have a decreased activity or carry gene duplications. However, there is a need for guidelines to translate different CYP2D6 allele combinations into phenotypes. We hereby summarize the current state of the knowledge concerning the relationship between CYP2D6 genotype and phenotype. Clinical relevance of CYP2D6 variation is highlighted with respect to both drugs and putative endogenous ligands. Looking forward, we present a practical genotype interpretation tool, which may help to implement CYP2D6 pharmacogenetics in medical practice. Additionally, we discuss CYP2D6 activity measurement in the context of the recent efforts for multiplexed phenotyping of drug metabolism in vivo.

Keywords: Codeine, CYP2D6, genotype, pharmacogenetics, phenotype, predictive medicine, SSRI, tamoxifen, cytochrome P450 2D6 (CYP2D6), xenobiotics, analgesic codeine, antipsychotic drugs haloperidol, perphenazine, risperidone, tricyclic antidepressants, beta-blockers, antiarrhythmics, poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), ultrarapid metabolizer (UM), debrisoquine, sparteine, dextromethorphan (DM), selective serotonin reuptake inhibitors (SSRIs), metabolic ratio (MR), multiplexphenotyping, gas chromatography (GC), high-performance liquid chromatography (HPLC), paraxanthine, losartan, omeprazole, quinine, dextrometorphan, single nucleotide polymorphisms (SNP), polyacrylamide gel electrophoresis, allele-specific amplification, nortriptyline (NT), amitriptyline (AT), semiquantitative gene doses (SGD), activity score (AS), dextromethorphan MR, endoxifen, paroxetine, fluoxetine, Venlafaxine, quinidine, antiarrhythmic drug, intermediate metabolizers (IM), haloperidol, desipiramine, perhexiline, postpartum analgesia, morphine, Odesmethylvenlafaxine (ODV), nortripyline (NT), breast cancer