Paracetamol (acetaminophen) hepatotoxicity at overdose doses is due to accumulation of which toxic metabolite, produced when glucuronidation and sulfation pathways are saturated?

• A Para-aminophenol by CYP2E1
• B Glucuronide conjugate causing biliary obstruction
• C Sulfate conjugate accumulating in renal tubules
• D N-acetyl-p-benzoquinone imine (NAPQI) by CYP2E1 and CYP3A4 ✓

Explanation

At therapeutic doses, acetaminophen is predominantly conjugated with glucuronate and sulfate (non-toxic). A small fraction (~5%) undergoes CYP2E1/CYP3A4-mediated oxidation to NAPQI (N-acetyl-p-benzoquinone imine), a highly reactive electrophile that is normally rapidly detoxified by conjugation with glutathione (GSH) to a non-toxic mercapturic acid conjugate. At overdose, glucuronidation and sulfation are saturated, channeling more drug through CYP to NAPQI; when hepatic GSH is depleted, NAPQI covalently binds protein thiols causing hepatocyte necrosis (centrilobular, zone 3 — where CYP2E1 is most concentrated). N-acetylcysteine (NAC) works by replenishing GSH.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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