Drug Safety

, Volume 7, Supplement 1, pp 45–50 | Cite as

Possible Role of Free Radical Formation in Drug-Induced Agranulocytosis

  • Ronald P. Mason
  • Volker Fischer
Article

Summary

The use of clozapine†, a unique antipsychotic drug, has been restricted due to a 1 to 2% incidence of drug-induced agranulocytosis. Many other drugs, including paracetamol (acetaminophen), can cause agranulocytosis, although with a much lower incidence. Metabolic activation of these drugs by neutrophils or stem cells could be the molecular mechanism underlying this adverse effect. Drug oxidation by myeloperoxidase leads to free radical metabolite formation; these reactive free radicals can oxidise glutathione to a thiyl free radical, which in the presence of oxygen forms oxygen-derived free radicals.

In contrast to glutathione, when these free radical metabolites oxidise ascorbate an unreactive free radical is formed, which does not even react with oxygen. In both reactions, the free radical metabolite is reduced to the original drug, although ascorbate is the more effective reducing agent. Thus ascorbate, when coadministered with agranulocytosis-causing drugs, may inhibit free radical chain reactions and other free radical-mediated reactions, such as protein adduct formation, and thereby prevent drug-induced agranulocytosis.

Keywords

Paracetamol Agranulocytosis Thiyl Radical Glutathione Disulphide Anion Radical Formation 

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Copyright information

© Adis International Limited 1992

Authors and Affiliations

  • Ronald P. Mason
    • 1
  • Volker Fischer
    • 2
  1. 1.Laboratory of Molecular BiophysicsNational Institute of Environmental Health Sciences, National Institutes of HealthResearch Triangle ParkUSA
  2. 2.Drug Safety DepartmentSandoz Pharma LtdBasleSwitzerland

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