A patient receives an accidental overdose of acetaminophen. Hepatocytes in zone 3 (centrilobular) show coagulative necrosis. What is the primary mechanism of cell death in acetaminophen toxicity?

• A Acetaminophen directly inhibits Complex I of the electron transport chain, causing ATP depletion
• B NAPQI formation by CYP2E1 depletes glutathione, causing oxidative stress and mitochondrial dysfunction ✓
• C Acetaminophen sulfate conjugate activates Fas receptor on hepatocytes, triggering extrinsic apoptosis
• D Acetaminophen glucuronide accumulates in lysosomes, causing lysosomal membrane permeabilization

Explanation

At toxic doses, acetaminophen is metabolized by CYP2E1 (concentrated in zone 3) to the reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine). NAPQI rapidly depletes hepatocellular glutathione; once GSH is exhausted, NAPQI covalently binds proteins and lipids, generates reactive oxygen species, causes mitochondrial permeability transition, and triggers centrilobular hepatocyte necrosis. N-acetylcysteine replenishes GSH and is the antidote.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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