Parenteral iron formulations: A comparative toxicologic analysis and mechanisms of cell injury

Background: Multiple parenteral iron (Fe) formulations exist for administration to patients with end-stage renal disease. Although there are concerns regarding their potential toxicities, no direct in vitro comparisons of these agents exist. Thus, the present study contrasted pro-oxidant and cytotoxic potentials of four available Fe preparations: Fe dextran (Fe dext), Fe sucrose (Fe sucr), Fe gluconate (Fe gluc), and Fe oligosaccharide (Fe OS). Methods: Differing dosages (0.06 to 1 mg/mL) of each compound were added to either (1) isolated mouse proximal tubule segments, (2) renal cortical homogenates, or (3) cultured human proximal tubule (HK-2) cells (0.5- to 72-hour incubations). Oxidant injury (malondialdehyde generation) and lethal cell injury (percentage of lactate dehydrogenase release; tetrazolium dye uptake) were assessed. Effects of selected antioxidants (glutathione [GSH], catalase, dimethylthiourea (DMTU), and sodium benzoate also were assessed. Results: Each test agent induced massive and similar degrees of lipid peroxidation. Nevertheless, marked differences in cell death resulted (Fe sucr > > Fe gluc > Fe dext ≃ Fe OS). This relative toxicity profile also was observed in cultured aortic endothelial cells. Catalase, DMTU, and sodium benzoate conferred no protection. However, GSH and its constituent amino acid glycine blocked Fe sucr-mediated cell death. The latter was mediated by mitochondrial blockade, causing free radical generation and a severe adenosine triphosphate depletion state. Conclusions: (1) parenteral Fes are highly potent prooxidants and capable of inducing tubular and endothelial cell death, (2) markedly different toxicity profiles exist among these agents, and (3) GSH can exert protective effects. However, the latter stems from GSH's glycine content, rather than from a direct antioxidant effect.