Paracetamol (acetaminophen) hepatotoxicity in overdose is caused by the toxic metabolite NAPQI. This metabolite is generated by which cytochrome P450 enzyme, upregulated by chronic alcohol use?

• A CYP3A4
• B CYP2D6
• C CYP1A2
• D CYP2E1 ✓

Explanation

Normally, paracetamol is glucuronidated and sulfated (>95%). A small fraction is oxidised by CYP2E1 (and CYP3A4 to a lesser extent) to N-acetyl-p-benzoquinone imine (NAPQI), a reactive electrophile that is detoxified by conjugation with glutathione. Chronic alcohol induces CYP2E1, increasing NAPQI production; simultaneously, alcohol depletes glutathione, making hepatotoxicity worse at lower paracetamol doses in alcoholics. N-acetylcysteine replenishes glutathione.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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