Paracetamol (acetaminophen) hepatotoxicity occurs when therapeutic dose is exceeded. The reactive metabolite responsible for hepatocellular necrosis is NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is generated by:

• A Glucuronidation of acetaminophen forming a reactive acyl glucuronide
• B CYP2E1 (and CYP3A4) oxidation of acetaminophen to NAPQI ✓
• C Sulfation of acetaminophen generating a reactive sulfoconjugate
• D Monoamine oxidase B converting acetaminophen to NAPQI in hepatic microsomes

Explanation

Acetaminophen is primarily detoxified by glucuronidation (~60%) and sulfation (~30%). A minor fraction (~5-10%) is oxidised by CYP2E1 (primary at therapeutic doses) and CYP3A4 (important at high doses) to the highly reactive electrophile NAPQI. At therapeutic doses, NAPQI is rapidly conjugated with glutathione (GSH) and excreted as mercapturic acid conjugates. In overdose, glutathione stores are depleted, and NAPQI covalently binds to hepatocellular protein thiols causing zone 3 (centrilobular) necrosis. N-acetylcysteine (NAC) treatment replenishes GSH precursor. Glucuronidation and sulfation are detoxification pathways, not activation pathways for NAPQI.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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