Paracetamol (acetaminophen) hepatotoxicity results from saturation of glucuronidation and sulfation pathways, forcing excess drug through CYP2E1. Which toxic metabolite is generated and which endogenous molecule is depleted in its detoxification?

• A N-acetyl-p-benzoquinone imine (NAPQI) — depletes glutathione (GSH) ✓
• B Phenol metabolite — depletes NADPH
• C Acetaldehyde — depletes NAD+
• D Epoxide metabolite — depletes superoxide dismutase

Explanation

CYP2E1 oxidizes paracetamol to NAPQI (N-acetyl-p-benzoquinone imine), a highly electrophilic reactive intermediate. At therapeutic doses, NAPQI is rapidly detoxified by conjugation with hepatic glutathione (GSH). In overdose, GSH stores are depleted; NAPQI then covalently binds to cellular macromolecules (protein thiols), causing oxidative stress and centrilobular necrosis (zone 3 hepatocytes express highest CYP2E1). N-acetylcysteine (NAC) is the antidote — it replenishes GSH by providing cysteine substrate. CYP2E1 is also induced by alcohol and fasting (both increase hepatotoxicity risk).

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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