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[Biochemistry](https://durgical.com/en/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

- [Acetaminophen toxicity](https://durgical.com/en/conditions/acetaminophen-toxicity/)
- [Alcoholic liver disease (biochemistry)](https://durgical.com/en/conditions/alcoholic-liver-disease/)

## Related

- [NAPQI (N-acetyl-p-benzoquinone imine)](https://durgical.com/en/biochemistry/molecules/napqi/)
- [Glutathione (GSH)](https://durgical.com/en/biochemistry/molecules/glutathione/)
- [N-acetylcysteine (NAC)](https://durgical.com/en/biochemistry/molecules/n-acetylcysteine/)
- [Cytochrome P450 2E1 (CYP2E1, MEOS)](https://durgical.com/en/biochemistry/enzymes/cytochrome-p450-2e1/)
- [Cytochrome P450 3A4 (CYP3A4)](https://durgical.com/en/biochemistry/enzymes/cytochrome-p450-3a4/)
- [Glucuronidation](https://durgical.com/en/biochemistry/topics/glucuronidation/)
- [Xenobiotic biotransformation: phases I, II and III](https://durgical.com/en/biochemistry/topics/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.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: [Paracetamol ADME](https://reactome.org/PathwayBrowser/#/R-HSA-9753281) (Reactome, 2026); [Acetaminophen overdose: MedlinePlus Medical Encyclopedia](https://medlineplus.gov/ency/article/002598.htm) (MedlinePlus, US National Library of Medicine, 2026); [Acetaminophen: MedlinePlus Drug Information](https://medlineplus.gov/druginfo/meds/a681004.html) (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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