Acetaminophen (paracetamol) hepatotoxicity at overdose doses occurs because the major detoxification pathways are saturated. Which CYP450 enzyme produces the toxic intermediate, and what is that intermediate?

• A CYP2E1 → N-acetyl-p-benzoquinone imine (NAPQI) ✓
• B CYP3A4 → para-aminophenol
• C CYP2C9 → phenacetin
• D CYP1A2 → catechol

Explanation

At therapeutic doses, acetaminophen is predominantly conjugated with glucuronide (55%) and sulfate (35%), with <5% oxidized by CYP2E1 (and CYP3A4) to NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is immediately conjugated with glutathione. At overdose, glucuronidation and sulfation saturate, >10% goes through CYP2E1, depleting hepatic glutathione. Unquenched NAPQI arylates cellular proteins and mitochondrial membranes, causing zone 3 (centrilobular) necrosis. N-acetylcysteine replenishes glutathione precursors.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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