Generation of reactive oxygen species by hydroxyketone compounds

Abstract

Deferiprone (3-hydroxy-1,2-dimethyl-4-pyridone), a hydroxyketone compound with pyridine ring, is a water soluble, orally active iron chelator used for the therapy of Friedreichʼs ataxia and -thalassemia. Toxic effect of deferiprone was analyzed in relation to the generation of reactive oxygen species. 1. Deferiprone/iron complex inactivated aconitase, the most sensitive enzyme to oxidative stress. The inactivation was dependent on sodium azide, an inhibitor of catalase, indicating that deferiprone/iron complex can generate hydrogen peroxide as a principal product. Deferiprone was more effective on aconitase than maltol or kojic acid, hydroxyketone compounds with pyrane ring. 2. Deferiprone, maltol and kojic acid stimulated the atuooxidation of Fe²⁺ suggesting that these compounds promote the activation of dioxygen molecule by reduced iron. When chelating agents are used for iron storage disease, attention should be paid to the transition metal-complex mediated generation of reactive oxygen species.