Prooxidant activity of ferrioxamine in isolated rat hepatocytes and linoleic acid micelles

The complex iron-desferrioxamine (ferrioxamine) is considered chemically un reactive, and not able to participate in redox cycle reactions. Desferrioxa mine-dependent toxicity is, however, described in both human and animal stu dies. The aim of this work was to test the possibility that chelated iron, under certain circumstances, could enter redox reactions, giving an explana tion of desferrioxamine side effects, Carefully prepared ferrioxamine, to o btain a 1:1 desferrioxamine:iron ratio, was added to isolated rat hepatocyt es and to linoleic acid micelles. A strong prooxidant and cytotoxic effect was observed in the cells, also potentiating tert-butyl hydroperoxide-induc ed lipid peroxidation. In micelles, the prooxidant effect was observed only in the presence of ascorbate, which is oxidized during the process, giving rise to ascorbyl radical. Ferrioxamine, under the experimental conditions used, did not release iron, indicating that the prooxidant effect was due t o iron redox cycling. The addition of desferrioxamine prevented both ferrio xamine- and tert-butyl hydroperoxide-induced lipid peroxidation and cytotox icity. Concurrently, a nitroxide radical was detected, an indication of the radical scavenger activity of the hydroxamic moiety. No radical species wa s observed when ferrioxamine was added to the same system. The prooxidant e ffect of ferrioxamine gives a possible explanation of the reported human an d animal desferrioxamine toxicity. When, in compartmentalized regions, the ratio of desferrioxamine:metal reaches 1:1, ferrioxamine is formed. In the absence of metal-free desferrioxamine, ferrioxamine can participate in redo x cycling reactions, initiating lipid peroxidation and cytotoxicity.