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 approximately 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 pro-oxidants 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.
Zager
Richard A
RA
Department of Medicine, University of Washington, Seattle, WA, USA. dzager@fhcrc.org
Johnson
Ali C M
AC
Hanson
Sherry Y
SY
Wasse
Haimanot
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D002461:Cell Line, Transformed; D002470:Cell Survival / Q000187:drug effects; D002712:Chlorides; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005290:Ferric Compounds / Q000378:metabolism / Q000633:toxicity; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; D006801:Humans; D007501:Iron / Q000378:metabolism / Q000633:toxicity*; D007505:Iron-Dextran Complex / Q000378:metabolism / Q000633:toxicity; D007676:Kidney Failure, Chronic / Q000378:metabolism / Q000473:pathology* / Q000628:therapy; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D009844:Oligosaccharides / Q000378:metabolism / Q000633:toxicity; D016877:Oxidants / Q000378:metabolism / Q000633:toxicity; D010288:Parenteral Nutrition / Q000379:methods
D002712:Chlorides; D005290:Ferric Compounds; D009844:Oligosaccharides; D016877:Oxidants; D008315:Malondialdehyde; D007505:Iron-Dextran Complex; D007501:Iron; D000077605:Ferric Oxide, Saccharated; D005937:Glucaric Acid; C024555:ferric chloride; C035552:ferric gluconate