Paracetamol (acetaminophen, APAP, N-acetyl-p-aminophenol, C₈H₉NO₂) is non-acidic (pKa 9.5) — explaining its exceptional gastric tolerance — and structurally simpler than aspirin or ibuprofen. Despite 70 years of clinical use, its mechanism of action remains actively debated.
The competing hypotheses
COX-3 hypothesis: A COX-1 splice variant expressed mainly in the CNS, selectively inhibited by paracetamol. Lost favor after human relevance was questioned. Endocannabinoid hypothesis (strongest current evidence): Paracetamol deacetylates in the brain to p-aminophenol, which reacts with arachidonic acid to form AM404 (N-arachidonoyl-phenolamine) — a potent TRPV1 agonist and anandamide reuptake inhibitor. Serotoninergic hypothesis: Paracetamol activates descending inhibitory pain pathways using serotonin.
The elegant biochemistry of hepatotoxicity
At therapeutic doses: Paracetamol is metabolized mainly by glucuronidation (~60%) and sulfation (~30%). Only 5–10% is processed by CYP2E1 to the reactive metabolite NAPQI (N-acetyl-p-benzoquinoneimine), which is immediately captured by hepatic glutathione and excreted harmlessly.
At toxic doses (>7.5–10 g in adults): Glucuronidation and sulfation pathways saturate. CYP2E1 processes a much larger fraction, producing NAPQI that exhausts glutathione reserves. Free NAPQI reacts covalently with hepatocyte proteins — especially mitochondrial proteins — producing mitochondrial dysfunction, oxidative stress, and centrilobular hepatic necrosis.
The antidote is N-acetylcysteine (NAC) — a glutathione precursor. Administered within 8–10 hours of ingestion, it prevents virtually all hepatic damage.