Biochemistry · Topic
Acetaminophen metabolism and NAPQI !
At therapeutic doses acetaminophen is conjugated and excreted; in overdose those routes saturate and NAPQI destroys the liver.
Updated 2026-11-01
Key facts
- Main route: glucuronidation (UGT) and sulfation (SULT); together they clear most of the drug.
- A small fraction is oxidised by CYP2E1, CYP3A4 and CYP1A2 to NAPQI, which glutathione neutralises at once.
- In overdose conjugation saturates, more NAPQI is made and glutathione runs out.
- Free NAPQI binds mitochondrial proteins: oxidative stress, mitochondrial failure and centrilobular (zone 3) necrosis.
- It is the most frequent cause of acute liver failure in the United States and Europe.
In detail
- Acetaminophen is absorbed in the gut and reaches the liver through the portal vein.
- UGTs attach glucuronic acid and SULTs sulfate: it leaves in the urine without harm.
- P450s (mainly CYP2E1) oxidise a part of it to NAPQI.
- Glutathione S-transferase joins NAPQI to glutathione; the conjugate leaves as mercapturic acid.
- In overdose, conjugation saturates, NAPQI rises and glutathione falls to about 30 %.
- Free NAPQI attacks the cysteines of mitochondrial proteins: JNK is activated, the transition pore opens and the cell dies by necrosis.
- N-acetylcysteine supplies cysteine, rebuilds glutathione and breaks the chain if it arrives in time.
- Also called
- Paracetamol
Clinical notes
- Higher risk with chronic alcohol use (more CYP2E1, less glutathione), fasting, malnutrition and enzyme inducers.
- Many over-the-counter combinations contain acetaminophen: unintentional stacking is a frequent cause of overdose.
- Transaminases rise at 24–36 hours and can exceed several thousand; peak injury comes at 3–4 days.
- The Rumack-Matthew nomogram, using a level taken from 4 hours after a single ingestion, guides N-acetylcysteine use.
Related conditions
Related
- NAPQI (N-acetyl-p-benzoquinone imine)
- Glutathione (GSH)
- N-acetylcysteine (NAC)
- Cytochrome P450 2E1 (CYP2E1, MEOS)
- Cytochrome P450 3A4 (CYP3A4)
- Glucuronidation
- Xenobiotic biotransformation: phases I, II and III
Test yourself
Think of the answer, then tap the question to see it.
Which two conjugations clear most acetaminophen?
Glucuronidation and sulfation.
When does NAPQI liver injury begin?
When hepatic glutathione is depleted (around 30 % of normal) and NAPQI is left free.
Why does fasting raise the risk of acetaminophen toxicity?
It lowers glutathione and the reserves for glucuronidation, and induces CYP2E1.
What is the Rumack-Matthew nomogram for?
To decide on N-acetylcysteine from the acetaminophen level and the hours since a single ingestion.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Paracetamol ADME (Reactome, 2026); Acetaminophen overdose: MedlinePlus Medical Encyclopedia (MedlinePlus, US National Library of Medicine, 2026); Acetaminophen: MedlinePlus Drug Information (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.