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Paracetamol overdose: metabolic pathways

Paracetamol overdose: metabolic pathways

The liver normally metabolises paracetamol predominantly via conjugation with glucuronic acid and sulphate to form non-toxic metabolites. A small proportion is oxidised by cytochrome P450 enzymes (particularly CYP2E1) to produce a highly reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).

Under normal conditions:
  • NAPQI is rapidly detoxified by conjugation with glutathione
  • This forms non-toxic cysteine and mercapturic acid metabolites

In overdose:
  • Glucuronidation and sulphation pathways become saturated
  • A greater proportion is metabolised via the P450 system
  • This leads to excessive production of NAPQI

When glutathione stores are depleted (typically <30% of normal):
  • NAPQI accumulates
  • It binds covalently to cellular proteins
  • This causes oxidative stress, mitochondrial dysfunction, and hepatocellular necrosis
  • Renal tubular injury may also occur

Pathophysiology of paracetamol overdose

N-acetylcysteine is used in the management of paracetamol overdose as it is a precursor of glutathione, replenishing hepatic glutathione stores and enhancing detoxification of NAPQI. It may also have additional antioxidant and cytoprotective effects.

Clinical implication:
  • Patients taking cytochrome P450 enzyme inducers (e.g. phenytoin, carbamazepine, rifampicin) or with chronic alcohol use produce more NAPQI
  • Therefore, a lower threshold is used for initiating treatment in these patients
+PassMedicine Notes

The liver normally metabolises paracetamol predominantly via conjugation with glucuronic acid and sulphate to form non-toxic metabolites. A small proportion is oxidised by cytochrome P450 enzymes (particularly CYP2E1) to produce a highly reactive toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI).

Under normal conditions:
  • NAPQI is rapidly detoxified by conjugation with glutathione
  • This forms non-toxic cysteine and mercapturic acid metabolites
In overdose:
  • Glucuronidation and sulphation pathways become saturated
  • A greater proportion is metabolised via the P450 system
  • This leads to excessive production of NAPQI

When glutathione stores are depleted (typically



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