Paracetamol overdose causes centrilobular hepatic necrosis because a reactive metabolite depletes glutathione stores. Which metabolite and which antidote correctly complete this statement?

• A AM404 formed by FAAH; N-acetylcysteine blocks TRPV1 receptors
• B NAPQI formed by CYP2E1; N-acetylcysteine replenishes glutathione ✓
• C NAPQI formed by UGT2B7; methionine induces glutathione synthase
• D Hydroxylamine formed by CYP3A4; N-acetylcysteine chelates the metabolite

Explanation

B small fraction of paracetamol is oxidized by CYP2E1 to N-acetyl-p-benzoquinone imine (NAPQI), which is normally detoxified by conjugation with glutathione. In overdose, glutathione is exhausted and NAPQI binds hepatocyte proteins, producing centrilobular necrosis. N-acetylcysteine restores hepatic glutathione and is most effective within 8 to 10 hours of ingestion. AM404 is a proposed central metabolite relevant to analgesia, not hepatotoxicity, which kills option A.

Reference: Katzung's Basic and Clinical Pharmacology, 15th ed.

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