Paracetamol (acetaminophen) hepatotoxicity occurs at overdose. The toxic metabolite NAPQI is formed by which CYP450 enzyme, and its detoxification requires:

• A CYP3A4; detoxified by glucuronidation
• B CYP1A2; detoxified by sulfate conjugation
• C CYP2D6; detoxified by N-acetylation
• D CYP2E1/CYP3A4; detoxified by conjugation with glutathione ✓

Explanation

N-acetyl-p-benzoquinone imine (NAPQI) is the toxic reactive metabolite of paracetamol formed by CYP2E1 (predominantly) and CYP3A4 at overdose doses, when glucuronidation and sulfation pathways are saturated. NAPQI is a highly reactive electrophile that is normally detoxified by conjugation with reduced glutathione (GSH), forming a mercapturic acid conjugate excreted in urine. When hepatic GSH is depleted (as in overdose), NAPQI binds covalently to protein cysteine residues causing hepatocyte necrosis (centrilobular, zone 3 — maximum CYP2E1 expression). N-acetylcysteine (NAC) treatment replenishes GSH. CYP1A2 metabolises caffeine and theophylline; CYP2D6 metabolises codeine.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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