A patient with acetaminophen overdose develops centrilobular hepatic necrosis. The key mechanism of hepatocyte injury is best described as:

• A Direct inhibition of cytochrome c oxidase by acetaminophen
• B Immune-mediated T-lymphocyte killing of hepatocytes expressing drug-hapten complexes
• C Receptor-mediated apoptosis via TNF-R1 activation by acetaminophen metabolites
• D CYP2E1-mediated conversion to NAPQI depleting glutathione, causing oxidative membrane injury ✓

Explanation

Acetaminophen is converted by CYP2E1 (and CYP3A4) to the highly reactive N-acetyl-p-benzoquinone imine (NAPQI). At therapeutic doses, NAPQI is conjugated with glutathione (GSH). In overdose, GSH is depleted, and NAPQI covalently binds cellular proteins and lipids causing mitochondrial dysfunction, oxidative stress, and centrilobular hepatocyte necrosis. The centrilobular predominance reflects the high CYP2E1 concentration in zone 3.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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