Genotoxicity of iron chelators in L5178Y mouse lymphoma cells.
To further study the mechanism of observed iron mutagenicity and cellular toxicity, a number of different iron chelators were evaluated to select a compound that was not mutagenic and had limited toxicity to mouse lymphoma cells. A series of iron chelators including those used clinically, those under development for clinical applications, and those used in nonclinical applications were evaluated. The mutagenic activity of the iron chelators was assessed in L5178Y mouse lymphoma cells. Eight of the 12 iron chelators that were tested induced mutagenic responses both with and without the addition of S9. Among those chelators used clinically or developed for clinical use, the only compound that did not induce a mutagenic response was the starch deferoxamine conjugate. In contrast, deferoxamine mesylate showed the highest toxicity in this group of chemicals and the concentrations leading to toxicity and mutagenicity between the activated and nonactivated assays were not significantly different. The other three chelators that were not mutagenic were Na2EDTA, phytic acid, and ferrozine.
Whittaker
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Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204, USA. paul.whittaker@cfsan.fda.gov
Seifried
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San
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Clarke
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Dunkel
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D000818:Animals; D000077543:Deferiprone; D004492:Edetic Acid / Q000031:analogs & derivatives*; D007502:Iron Chelating Agents / Q000633:toxicity*; D008223:Lymphoma / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D009152:Mutagenicity Tests / Q000379:methods; D010618:Phenanthrolines / Q000633:toxicity; D011728:Pyridones / Q000633:toxicity; D011929:Razoxane / Q000633:toxicity; D014407:Tumor Cells, Cultured
D007502:Iron Chelating Agents; D010618:Phenanthrolines; D011728:Pyridones; D000077543:Deferiprone; C037740:N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid; D011929:Razoxane; D004492:Edetic Acid; C025205:1,10-phenanthroline