I. GENERAL OVERVIEW
Many clinically important differences in drug response are caused by polymorphisms in genes encoding cytochrome P450 (CYP450) enzymes. These enzymes are responsible for the phase I metabolism of most commonly used drugs.
Because these polymorphisms are common in the population, they represent polymorphic monogenic pharmacogenetic defects.
II. CYP450 SUPERFAMILY – GENERAL CHARACTERISTICS
What is the CYP450 system?
The cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing monooxygenases, primarily located in the liver, that catalyze:
- oxidation,
- reduction,
- hydroxylation of drugs and xenobiotics.
Why CYP polymorphisms matter
Genetic variation in CYP genes leads to different metabolic phenotypes, which directly affect:
- plasma drug levels,
- efficacy,
- toxicity,
- risk of adverse drug reactions.
Metabolizer Phenotypes
III. CYP2D6
CYP2D6 metabolizes ~25% of commonly prescribed drugs, despite representing a small proportion of hepatic CYP enzymes.
Drugs Metabolized by CYP2D6
- Antidepressants (TCAs, SSRIs)
- Antipsychotics
- Beta-blockers
- Opioids (codeine, tramadol)
- Antiarrhythmics
Genetic Variability
- Gene deletions → poor metabolizers
- Gene duplications → ultrarapid metabolizers
Pathophysiology
- 1. CYP2D6 activity determines drug activation or inactivation.
- 2. Poor metabolizers accumulate parent drug → toxicity.
- 3. Ultrarapid metabolizers clear drug rapidly or overproduce active metabolites.
Clinical Examples
- Codeine:
- PM → inadequate analgesia
- UM → excessive morphine production → toxicity
- Antidepressants → increased side effects in PMs