The hepatotoxicity of paracetamol (acetaminophen) overdose is mediated by a reactive intermediate. Which CYP450 isoform is PRIMARILY responsible for its conversion to the toxic metabolite NAPQI?
- A CYP3A4
- B CYP2E1 (and CYP3A4 at lower contribution) ✓
- C CYP1A2
- D CYP2C9
Correct answer: B. CYP2E1 (and CYP3A4 at lower contribution)
Explanation
N-acetyl-p-benzoquinone imine (NAPQI) is generated primarily by CYP2E1 (the major contributor) and CYP3A4. At therapeutic doses, NAPQI is rapidly detoxified by conjugation with glutathione (GSH). In overdose, hepatic GSH is depleted and NAPQI covalently binds cellular proteins and mitochondrial membranes, causing zone 3 (centrilobular) necrosis. CYP2E1 is also induced by chronic alcohol use — explaining alcoholics' heightened paracetamol hepatotoxicity.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
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