CYP450
Summary
Cytochrome P450 (CYP450) enzymes are a superfamily of heme-containing enzymes located primarily in the liver (smooth ER) that catalyze phase I oxidative metabolism of drugs, toxins, and endogenous compounds (steroids, bile acids). They are critical for drug clearance and are frequently induced or inhibited, leading to significant drug-drug interactions on Step 1/2.
Detail
CYP450 enzymes perform oxidation, reduction, and hydrolysis reactions (phase I metabolism), often converting lipophilic drugs into more polar metabolites for further phase II conjugation and excretion. Key isoforms tested on boards include CYP3A4 (metabolizes ~50% of drugs), CYP2D6 (genetic polymorphisms affect codeine, tricyclics, beta-blockers metabolism), CYP2C9 (warfarin, phenytoin), and CYP1A2 (caffeine, theophylline).
Inducers (increase enzyme activity, decrease drug levels) - classic mnemonic 'barbs and other Cs': Barbiturates, carBAMazepine, phenytoin, rifampin, griseofulvin, chronic alcohol use, St. John's wort, smoking (CYP1A2). Inducers can cause treatment failure (e.g., OCP failure with rifampin) or increased toxic metabolite production.
Inhibitors (decrease enzyme activity, increase drug levels, risk of toxicity) - mnemonic includes: Sodium valproate, Isoniazid, Cimetidine/Ciprofloxacin, Ketoconazole/other azoles, Erythromycin/other macrolides, Grapefruit juice, Amiodarone, Ritonavir/protease inhibitors. Classic exam scenario: patient on warfarin develops bleeding after starting an antibiotic (macrolide) that inhibits CYP metabolism, increasing INR.
Genetic polymorphisms are clinically relevant: poor CYP2D6 metabolizers get inadequate analgesia from codeine (fails to convert to morphine) but may have toxicity from tricyclic antidepressants. CYP2C19 polymorphisms affect clopidogrel activation, causing reduced antiplatelet effect in poor metabolizers.
Drugs metabolized by CYP3A4 are particularly important due to grapefruit juice interactions (inhibits intestinal CYP3A4, increasing bioavailability of many drugs like statins, calcium channel blockers, cyclosporine).
Understanding CYP450 is essential for predicting drug interactions, adjusting dosing, and explaining variable drug responses among individuals (pharmacogenomics).
Sources
- Katzung's Basic & Clinical Pharmacology
- First Aid for the USMLE Step 1
- Goodman & Gilman's The Pharmacological Basis of Therapeutics
- USMLE-Rx Pharmacology
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