CYP2D6

Cytochrome P450 family 2 subfamily D member 6 (CYP2D6) is an important gene in the field of pharmacogenomics. It encodes a cytochrome P450 enzyme that metabolises about 20% of commonly prescribed medicines, including antidepressants, antipsychotics, analgesics and anticancer drugs.

CYP2D6 is a highly variable (polymorphic) gene: more than 170 haplotypes have been characterised for their impact on metabolism. This genetic heterogeneity is associated with significant pharmacokinetic variation between individuals, which impacts upon both efficacy and the risk of adverse effects.

• The Human Genome Organisation (HUGO) Gene Nomenclature Committee’s approved name for this gene is cytochrome P450 family 2 subfamily D member 6 (CYP2D6).
• CYP2D6 is located at chromosome 22q13.2.
• It contains nine exons, spanning 4,408 base pairs of DNA.
• It is a member of a supergene family that encodes the cytochrome P450 (CYP) enzymes. CYP enzymes metabolise endogenous and exogenous compounds.

• Drug metabolism by the CYP2D6 enzyme contributes to both the activation of prodrugs (such as codeine) and the deactivation of active drugs (such as amitriptyline).
• Among major drug metabolising CYP enzymes, CYP2D6 is the only non-inducible enzyme and so its function is not increased by other drugs.
• However, drug interactions owing to co-medications that inhibit CYP2D6 can alter the pharmacokinetic profile for drugs metabolised by CYP2D6. For example, it can be strongly inhibited by fluoxetine.

The highly polymorphic CYP2D6 enzyme metabolises many commonly prescribed medicines. The plasma concentration of a drug (or its metabolites) can vary significantly between patients because of heterogeneity in enzyme activity, which in turn can be predicted by genomic tests for functionally important variants (such as single nucleotide variants, splicing variants and copy number variants caused by gene duplication or deletion events).

Haplotypes are defined using star (*) allele nomenclature, with CYP2D6*1 being the reference allele. A full list of variants that define each star allele is curated and published by PharmGKB.

CYP2D6 star alleles are usually categorised according to an assigned activity score, which reflects whether the allele is expected to have normal, decreased, increased or no function. In turn, the combination of CYP2D6 alleles an individual has (also referred to as a genotype or diplotype) defines their genetically predicted CYP2D6 metaboliser phenotype.

Four categories for an individual’s CYP2D6 metaboliser phenotype were recently agreed upon by international working groups:

• poor;
• intermediate;
• normal; and
• ultra-rapid.

Please note that some guidelines also include a fifth category: rapid metaboliser.

An individual’s CYP2D6 genetically predicted metaboliser phenotype can be used to guide clinical prescribing decisions.

The Clinical Pharmacogenetics Implementation Consortium (CPIC) has published guidelines based on CYP2D6 genotype for the following drugs and drug classes:

• atomoxetine;
• opioids;
• ondansetron and tropisetron;
• selective serotonin reuptake inhibitors (SSRIs);
• tamoxifen; and
• tricyclic antidepressants.

An individual’s CYP2D6 predicted phenotype is based on the two alleles of their genotype (diplotype).

An example of the CYP2D6 genotype-to-predicted metaboliser phenotype translation process using CPIC guidelines is that a CYP2D6 genotype (diplotype) of 1*x3/*5 has a metaboliser phenotype of ultra-rapid and its priority notation is ‘abnormal/priority/high risk’.

Please note that the 1* allele is a reference allele but the nomenclature 1*x 3 indicates a gene multiplication event, which results in ultra-rapid enzyme activity. The CYP2D6 gene is subject to many copy number variants.

There are substantial differences in CYP2D6 allele frequencies between and within worldwide populations. The frequency of specific alleles in populations can inform the utility of pharmacogenomic testing, however, clinical recommendations are based on an individual’s genetically predicted metaboliser phenotype.

For clinicians

• Pharmacogene Variation Consortium (PharmVar)
• PharmGKB: Gene-specific Information Tables for CYP2D6
• PHG Foundation: Explaining pharmacogenomics (video, two minutes, 16 seconds)
• The Clinical Pharmacogenetics Implementation Consortium (CPIC): Guidelines
• US National Library of Medicine: CYP2D6 overview: Allele and phenotype frequencies

References:

• Caudle KE, Sangkuhl K, Whirl-Carrillo M and others. ‘Standardizing CYP2D6 genotype to phenotype translation: Consensus recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group’. Clinical and Translation Science 2020: volume 13, issue 1, pages 116–124. DOI: 10.1111/cts.12692
• Ingelman-Sundberg M, Sim SC, Gomez A and others. ‘Influence of cytochrome P450 polymorphisms on drug therapies: Pharmacogenetic, pharmacoepigenetic and clinical aspects’. Pharmacology & Therapeutics 2007: volume 116, issue 3, pages 496–526. DOI: 10.1016/j.pharmthera.2007.09.004