Increasing evidence indicates that the carcinogenicity of a metal depends on its """"""""cellular bioavailability""""""""; its ability to enter and accumulate in target cells and interact with genetic material. Iron has been implicated in the generation of highly reactive hydroxyl radicals, which can cause damage to DNA directly. The ferric form of the metal chelator ferric-nitrilotriacetate (FeNTA) has been reported to induce kidney tumors, potentiate an excessive excretion of essential urinary metals and cause a diabetic-like iron overload syndrome similar to that seen in human idiopathic hemochromatosis. We have used FeNTA to study mechanisms of metal- induced cancerous precancerous lesions using a rat model. Male rats received daily injections of ferric-nitrilotriacetate (FeNTA) for 9 weeks; control animals received equivalent amounts of nitrilotriacetate, ferric nitrate, iron dextran or saline. Protein and glucose were detected in the urine of FeNTA animals beginning at 4 weeks and persisted until the injections were terminated. A protein detected in the urine of FeNTA animals by polyacrylamide electrophoresis was determined to be the iron binding protein, transferrin by Western blot analysis. The excessive excretion of zinc, copper and iron in the FeNTA treated animals returned to baseline levels within 2 to 3 weeks after terminating the injections. FeNTA induced tubular renal adenocarcinomas in 60% of the surviving animals; no tumors were detected in controls. Preneoplastic lesions in the livers of several FeNTA animals were detected by gamma-glutamyl transpeptidase positive foci. Tissue distribution of iron, tissue metallothionein, and the activity of radical scavenging enzymes will be determined, since metalloproteins and antioxidant enzymes may affect metal induced free radical damage to DNA. A subset of the FeNTA dosed animals have been used to develop and refine magnetic resonance imaging (MRI) techniques to monitor kidney tumor growth over extended periods of time in the live animal.
