Paracetamol (acetaminophen) overdose causes hepatotoxicity primarily through which mechanism?

• A Direct inhibition of mitochondrial fatty acid oxidation causing hepatic steatosis
• B Saturation of glucuronidation/sulphation pathways generating NAPQI, which depletes glutathione and binds hepatic proteins covalently ✓
• C Induction of cytochrome P450 CYP2E1 leading to oxidative stress
• D Accumulation of paracetamol-glucuronide conjugate causing cholestatic liver injury

Explanation

At therapeutic doses, paracetamol is conjugated by glucuronidation and sulphation; a minor fraction is oxidised by CYP2E1/CYP3A4 to NAPQI (N-acetyl-p-benzoquinoneimine), which is detoxified by hepatic glutathione. In overdose, glucuronidation and sulphation are saturated, shunting more drug through the CYP pathway. NAPQI production exceeds glutathione stores; free NAPQI covalently binds hepatocyte proteins and mitochondrial membranes, causing centrilobular necrosis. N-acetylcysteine replenishes glutathione and is the antidote.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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