In acetaminophen hepatotoxicity, the toxic metabolite responsible for cell injury is NAPQI (N-acetyl-p-benzoquinone imine). When glutathione stores are depleted, NAPQI causes cell death primarily by:
- A Immune-mediated hepatocyte destruction via hapten formation
- B Bile canalicular obstruction causing cholestatic pattern
- C Covalent binding to cellular proteins and mitochondrial dysfunction causing centrilobular necrosis ✓
- D Direct inhibition of cytochrome c oxidase (complex IV) causing peripheral zone necrosis
Explanation
NAPQI generated by CYP2E1 and CYP3A4 is normally conjugated with glutathione. When glutathione is depleted (by overdose or alcoholism), NAPQI covalently binds hepatocyte proteins and mitochondrial components, uncoupling oxidative phosphorylation, generating reactive oxygen species, and triggering mitochondrial permeability transition, resulting in hepatocyte necrosis centered on zone 3 (centrilobular) where CYP2E1 activity is highest. It is primarily a direct toxic mechanism, not immune-mediated (though some drug hypersensitivity hepatitis is immune). N-acetylcysteine treatment replenishes GSH stores.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.