CYP2D6 Gene

The CYP2D6 gene encodes cytochrome P450 2D6, an important enzyme in the cytochrome P450 family that is involved in the metabolism of a wide range of clinically relevant drugs. Located on chromosome 22q13.2, the CYP2D6 gene is highly polymorphic, meaning it exhibits a large number of genetic variations that significantly affect enzyme activity. Because of this variability, CYP2D6 is a major focus of pharmacogenetics, the study of how genes influence individual responses to medications.

Structure and Function

• Protein Product: CYP2D6 belongs to the cytochrome P450 superfamily, a group of enzymes primarily responsible for the oxidative metabolism of drugs and endogenous compounds.
• Expression: It is predominantly expressed in the liver, but also found in the small intestine, brain, and other tissues.
• Enzymatic Role: CYP2D6 catalyses hydroxylation and demethylation reactions, making drugs more water-soluble and aiding in their excretion.
• Substrate Specificity: Despite accounting for only a small proportion of total hepatic cytochrome P450 enzymes (~2–4%), CYP2D6 metabolises about 20–25% of clinically used drugs.

Drugs Metabolised by CYP2D6

CYP2D6 acts on a broad spectrum of drugs across different therapeutic classes, including:

• Antidepressants: e.g., fluoxetine, paroxetine, venlafaxine, tricyclic antidepressants.
• Antipsychotics: e.g., risperidone, haloperidol, aripiprazole.
• Beta-blockers: e.g., metoprolol, propranolol.
• Opioids: e.g., codeine, tramadol, hydrocodone (CYP2D6 converts codeine to morphine, its active metabolite).
• Antiarrhythmics: e.g., flecainide, propafenone.
• Other drugs: e.g., tamoxifen (prodrug converted to its active form endoxifen).

Genetic Variability

The CYP2D6 gene is one of the most polymorphic in the human genome, with over 100 allelic variants identified. These variations include single nucleotide polymorphisms (SNPs), gene deletions, and gene duplications. Based on these variants, individuals can be classified into different metaboliser phenotypes:

• Poor Metabolisers (PMs): Have little or no CYP2D6 activity due to two non-functional alleles. Drugs metabolised by CYP2D6 may accumulate to toxic levels or fail to activate from prodrugs.
• Intermediate Metabolisers (IMs): Have reduced enzyme activity, leading to slower drug metabolism.
• Extensive Metabolisers (EMs): Represent the “normal” or reference group with fully functional enzyme activity.
• Ultra-rapid Metabolisers (UMs): Have multiple copies of the CYP2D6 gene, leading to excessive enzyme activity and unusually rapid drug metabolism.

Clinical Implications

Genetic variation in CYP2D6 has significant consequences in medicine:

• Drug Efficacy: For prodrugs like codeine and tamoxifen, poor metabolisers may not experience therapeutic effects due to insufficient conversion to active metabolites.
• Drug Toxicity: Poor metabolisers may suffer from adverse effects when drugs accumulate to high levels in the bloodstream.
• Overdose Risks: Ultra-rapid metabolisers may convert prodrugs too quickly, leading to potentially dangerous concentrations of active metabolites (e.g., respiratory depression from codeine).
• Personalised Medicine: Genetic testing for CYP2D6 status is increasingly recommended before prescribing certain drugs, allowing for tailored dosing strategies.

Pharmacogenetic Testing

Several guidelines, including those from the Clinical Pharmacogenetics Implementation Consortium (CPIC), recommend genetic testing for CYP2D6 to guide therapy with certain medications. Common tests identify key alleles, such as:

• CYP2D6 *1 (wild-type, normal activity).
• CYP2D6 *3, *4, *5, *6 (non-functional alleles common in European populations).
• Gene duplications such as CYP2D6 *1xN and *2xN (associated with ultra-rapid metabolism).

Testing helps clinicians select appropriate drugs and dosages, reducing risks of adverse drug reactions and improving treatment outcomes.

Population Distribution

The distribution of CYP2D6 metaboliser phenotypes varies across populations:

• Poor metabolisers are most common in European populations (~5–10%).
• Ultra-rapid metabolisers are more frequent in North African, Middle Eastern, and some Mediterranean populations (up to 20%).
• Considerable inter-ethnic variation exists, highlighting the importance of population-specific pharmacogenetic research.

Significance

The CYP2D6 gene is a central example of how genetic variability influences drug response. Understanding its role allows for:

• Optimisation of therapy through precision medicine.
• Reduction of adverse drug reactions, a major cause of hospitalisation and healthcare costs.