In acetaminophen (paracetamol) hepatotoxicity, the toxic metabolite NAPQI causes hepatocyte death by which primary mechanism?

• A Covalent binding to cellular proteins and depletion of glutathione causing oxidative stress and necrosis predominantly in zone III ✓
• B Direct mitochondrial membrane disruption causing coagulative necrosis of all hepatocytes
• C Autoimmune hepatitis triggered by NAPQI-protein adducts as neoantigens
• D Lipid peroxidation of hepatocyte membranes in zone I due to high CYP1A2 expression

Explanation

NAPQI (N-acetyl-p-benzoquinone imine), generated by CYP2E1 and CYP3A4 (predominant in zone III/centrilobular hepatocytes), is normally detoxified by conjugation with glutathione. In overdose, glutathione is depleted, allowing NAPQI to covalently bind cellular proteins and mitochondrial thiol groups, causing oxidative stress, mitochondrial dysfunction, and oncotic/necrotic cell death. Zone III necrosis is characteristic because CYP2E1 expression and lower glutathione concentration are highest in centrilobular hepatocytes. N-acetylcysteine (NAC) restores glutathione and is the antidote.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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