INDUCTION OF FREE-RADICALS AND TUMORS IN THE KIDNEYS OF WISTAR RATS BY FERRIC ETHYLENEDIAMINE-N,N'-DIACETATE

An iron chelate, ferric ethylenediamine-N,N'-diacetate [Fe(III)-EDDA], was found to produce hydroxyl radicals with hydrogen peroxide, as determined by both a deoxyribose degradation test and electron spin resonance. Hydroxyl radical production was inhibited not only by adding hydroxyl radical scavengers and catalase, but also by adding superoxide dismutase to the reaction mixture, suggesting that superoxide anion may be involved in the hydroxyl radical production. A single injection of Fe(III)-EDDA (10 mg Fe/kg body wt) to Wistar rats induced thiobarbituric acid reactivity in the kidneys and liver, Repeated injections of Fe(III)-EDDA (10 mg Fe/kg body wt, twice weekly for 3 months) induced a 40% incidence of renal tumors, including renal adenocarcinoma and renal adenoma, 1 year later. These results suggest that Fe(III)-EDDA is an effective free radical producer ia vitro and in vivo and that it may be useful in preparing animal models related to iron-dependent free radical damage. The results support our hypothesis that endogenous or exogenous iron, complexed with certain kinds of chelators, promotes free radical-dependent tissue damage and ultimately leads to carcinogenesis in the affected tissue.