A Review of the Important Role of CYP2D6 in Pharmacogenomics

Abstract

Cytochrome P450 2D6 (CYP2D6) is a critical pharmacogene involved in the metabolism of ~20% of commonly used drugs across a broad spectrum of medical disciplines including psychiatry, pain management, oncology and cardiology. Nevertheless, CYP2D6 is highly polymorphic with single-nucleotide polymorphisms, small insertions/deletions and larger structural variants including multiplications, deletions, tandem arrangements, and hybridisations with non-functional CYP2D7 pseudogenes. The frequency of these variants differs across populations, and they significantly influence the drug-metabolising enzymatic function of CYP2D6. Importantly, altered CYP2D6 function has been associated with both adverse drug reactions and reduced drug efficacy, and there is growing recognition of the clinical and economic burdens associated with suboptimal drug utilisation. To date, pharmacogenomic clinical guidelines for at least 48 CYP2D6-substrate drugs have been developed by prominent pharmacogenomics societies, which contain therapeutic recommendations based on CYP2D6-predicted categories of metaboliser phenotype. Novel algorithms to interpret CYP2D6 function from sequencing data that consider structural variants, and machine learning approaches to characterise the functional impact of novel variants, are being developed. However, CYP2D6 genotyping is yet to be implemented broadly into clinical practice, and so further effort and initiatives are required to overcome the implementation challenges and deliver the potential benefits to the bedside.

Keywords: CYP2D6; drug metabolism; pharmacogenomics; population variability; structural variation.

Figure 1

Venn Diagram showing recognised (non-HLA) pharmacogenes according to their association with drugs used in different therapeutic areas. CYP2D6 overlaps with four distinct therapeutic areas. BCHE: Butyrylcholinesterase. CFTR: Cystic fibrosis transmembrane conductance regulator. CYP2B6, CYP2C9, CYP2C19, CYP3A5, CYP4F2: Members of cytochrome P450 superfamily. DPYD: Dihydropyrimidine dehydrogenase. F5: Factor 5. G6PD: Glucose-6-phosphate dehydrogenase. IFNL3: Interferon lambda 3. ITPA: Inosine triphosphate pyrophosphohydrolase. NAT2: N-Acetyltransferase 2. NUDT15: Nudix hydrolase 15. POLG: DNA polymerase subunit γ. RARG: Retinoic acid receptor γ. SLCO1B1: Solute carrier organic anion transporter family member 1B1. SLC28A3: Solute carrier family 28 member 3. TPMT: Thiopurine S-methyltransferase. UGT1A1: UDP-glucuronosyltransferases. VKORC1: Vitamin K epoxide reductase complex.

Figure 2

Summary of main CYP2D6 structural variant types. Adapted from PharmVar CYP2D6 Structural Variation document [47]. (A) shows the wildtype layout of CYP2D6, CYP2D7 and CYP2D8. (B) shows examples of structural variants involving CYP2D6. For simplicity, REP6, REP7 and downstream elements have been omitted in (B).

Figure 3

The 3D structure of CYP2D6 from different angles, annotated with the locations of notable star allele-defining variants (neon green). Images (A–C) show CYP2D6 from different angles. The images on the left and right show the molecular surface of CYP2D6 and ribbon model of CYP2D6, respectively. The central heme group is highlighted in the ribbon models. Molecular structures were generated and annotated using Research Collaboratory for Structural Bioinformatics (RCSB) Protein Data Bank (PDB) software [59].

Figure 4

This figure illustrates the CYP2D6-mediated conversion of codeine to morphine. This pathway results in the metabolism of 0–15% of codeine. Other metabolites codeine-6-glucuronide and norcodeine are metabolized by UGT2B4 and UGT2B7, and CYP3A4, respectively, accounting for remaining codeine metabolism. [96]. Secondary metabolites such as morphine-6-glucuronide are not shown for simplicity.

Figure 5

This figure provides a simplified overview focusing on the role of CYP2D6 in the formation of endoxifen. Over 90% of tamoxifen metabolism is CYP3A-mediated N-demethylation to the primary metabolite, N-desmethyltamoxifen, which can be oxidized further by CYP2D6 to endoxifen. Approximately 7% of tamoxifen metabolism is CYP2D6-mediated hydroxylation to 4-hydroxytamoxifen. There is high interindividual variation in endoxifen exposure, which is a significantly more potent anti-oestrogen compared to parent tamoxifen [101,109].