Paracetamol (acetaminophen) overdose causes hepatotoxicity through NAPQI formation. NAPQI is formed by CYP2E1. The reason therapeutic doses of paracetamol are safe but overdose is toxic is:

• A At therapeutic doses, CYP2E1 is saturated and paracetamol is exclusively metabolised by glucuronidation/sulfation; overdose overwhelms these pathways, forcing CYP2E1 utilisation
• B At therapeutic doses, NAPQI formed is rapidly conjugated with glutathione (GSH) to a non-toxic mercapturic acid; overdose depletes GSH, allowing free NAPQI to arylate cellular proteins ✓
• C Overdose induces CYP2E1 gene expression, specifically increasing NAPQI formation above a safe threshold
• D NAPQI at low concentrations is reduced back to paracetamol by quinone oxidoreductase; at high doses this enzyme is overwhelmed

Explanation

CYP2E1 produces NAPQI (N-acetyl-p-benzoquinone imine) even at therapeutic doses, but the liver's GSH pool (primarily synthesized from cysteine) rapidly conjugates NAPQI to form non-toxic cysteine and mercapturic acid conjugates for urinary excretion. In overdose, massive NAPQI generation depletes hepatic GSH faster than it can be replenished; free NAPQI covalently arylates thiol groups on mitochondrial proteins, causing mitochondrial dysfunction, oxidative stress, and hepatocyte necrosis. N-acetylcysteine works as antidote by replenishing cysteine for GSH synthesis.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.