Gene Number: 1565

Location: 22q13.2

Key Functions: Drug metabolism, detoxification, CYP450 enzymatic activity

The CYP2D6 gene, located on chromosome 22q13.2, encodes cytochrome P450 2D6, one of the most pharmacologically significant enzymes within the cytochrome P450 superfamily. Despite representing only a small fraction of total hepatic CYP content (approximately 2–4%), CYP2D6 is responsible for metabolizing 20–25% of all clinically used drugs, underscoring its critical role in xenobiotic clearance and personalized medicine.

Biochemically, CYP2D6 catalyzes oxidative metabolism reactions such as hydroxylation, O-demethylation, and N-dealkylation, influencing the pharmacokinetics of a broad array of drugs. These include antidepressants (fluoxetine, paroxetine, venlafaxine), antipsychotics (risperidone, haloperidol), opioid analgesics (codeine, tramadol), beta-blockers (metoprolol, propranolol), and antiarrhythmics (flecainide, propafenone). Its activity determines whether drugs are inactivated or bioactivated, as exemplified by codeine’s conversion into morphine—a process entirely dependent on CYP2D6.

Genetically, CYP2D6 exhibits extreme polymorphism, with over 150 known allelic variants and numerous copy number variations (CNVs) that shape enzymatic activity. These variants define distinct metabolizer phenotypes:

• Poor metabolizers (PM) carry two nonfunctional alleles (e.g., 3, 4, 5, 6), leading to little or no enzyme activity.

• Intermediate metabolizers (IM) possess one reduced-function allele (e.g., 10, 41).

• Normal (extensive) metabolizers (NM) have two functional alleles (e.g., 1, 2).

• Ultra-rapid metabolizers (UM) carry multiple copies of functional alleles (e.g., 1xN, 2xN), resulting in markedly increased enzyme activity.

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These genetic distinctions have profound clinical implications. Poor metabolizers may experience drug accumulation and toxicity with standard doses of CYP2D6 substrates, while ultra-rapid metabolizers may show subtherapeutic responses or enhanced activation of prodrugs, occasionally leading to adverse reactions — such as opioid toxicity from rapid codeine conversion. The CYP2D6*4 allele, common in European populations, is a major determinant of poor metabolism, whereas CYP2D6*10, frequent in East Asian populations, causes reduced activity.

From a pharmacogenomic standpoint, CYP2D6 genotyping is integral to precision prescribing for drugs with narrow therapeutic indices or strong CYP2D6 dependence. Regulatory bodies such as the FDA and CPIC recommend genotype-guided dosing or drug substitution (e.g., alternative antidepressants or opioids) to avoid inefficacy or toxicity.

In essence, CYP2D6 represents one of the clearest illustrations of genetic individuality in pharmacology. Its vast allelic diversity and dose-dependent metabolic consequences highlight how variations in a single gene can dictate therapeutic success or failure — making it a cornerstone in the evolution of personalized and genomically informed medicine.