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Mechanism of hepatotoxicity

Authoring team

Paracetamol has no hepatotoxicity in normal clinical doses.

The liver metabolises paracetamol by oxidation in the cytochrome P450 system. The reactive quinone derivative of paracetamol is removed by reaction with the sulphydryl- containing compound, glutathione.

If glutathione is depleted then the quinone binds covalently to cellular proteins, resulting in hepatocyte death (it is an alkylating agent and causes centrilobular necrosis).

Administration of sulphydryl-containing compounds, such as n-acetyl cysteine or methionine, replenishes the glutathione levels in the hepatocytes and protects against paracetamol poisoning.

Note that the induction of liver enzymes by previous barbiturate and/or alcohol leads to a greater production of intermediate metabolite and thus potentiates toxicity.

Reference

  1. Chidiac A et al. Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease. Expert Opin Drug Metab Toxicol. 2023 Jan-Jun;19(5):297-317.

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