Paracetamol (acetaminophen) hepatotoxicity occurs when the minor metabolic pathway producing NAPQI (N-acetyl-p-benzoquinone imine) overwhelms glutathione stores. Which CYP isoform is primarily responsible for NAPQI formation?
- A CYP1A2
- B CYP2E1 (and CYP3A4 at high doses) ✓
- C CYP2D6
- D CYP2C9
Explanation
At therapeutic doses, >90% of paracetamol is conjugated with glucuronate or sulphate and excreted safely. A small fraction is oxidised by CYP2E1 (and CYP3A4 at toxic doses) to the reactive electrophile NAPQI. NAPQI is normally detoxified by conjugation with glutathione. In overdose, or with chronic alcohol use (which induces CYP2E1), NAPQI production exceeds glutathione capacity, and free NAPQI covalently binds hepatocyte proteins, causing centrilobular necrosis. N-acetylcysteine treatment replenishes glutathione. CYP2D6 metabolises codeine and antidepressants; CYP2C9 metabolises warfarin and phenytoin; CYP1A2 handles caffeine and theophylline.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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