To investigate the effect of subsequently absorbed metal chelators on recently absorbed 59Fe, duodenal segments from iron-deficient and iron-adequate rats were perfused ex vivo until the 59Fe tissue load had reached a steady state. Subsequently, the segments were perfused with 3 model chelators and their iron complexes: nitrilotriacetic acid (NTA), ethylenediaminetetraacetic acid (EDTA) and citrate. Of these, NTA and EDTA bind iron much tighter than citrate, and Fe-NTA complexes exchange iron within seconds while Fe-EDTA complexes need 48 h to reach equilibrium. Duodenal mucosa-to-serosa transport rates were comparable for all 3 chelators and correlated linearly with luminal concentration. Subsequent perfusion with increasing NTA, Fe-NTA(1:2) and EDTA concentrations mobilised increasing amounts of 59Fe from the duodenum. Mobilised 59Fe moved preferentially back into the luminal perfusate in iron-adequate segments. In iron-deficient segments, 59Fe preferentially continued the absorption process across the basolateral membrane. Fe-EDTA(1:1) hardly mobilised any 59Fe back into the lumen, though basolateral transfer increased at high concentrations. Citrate and Fe-citrate(1:1) mobilised 59Fe only at very high concentrations. This behaviour is in accordance with the rules of complex chemistry: strong, fast reacting ligands like NTA show most impact. Slowly reacting complexes like Fe-EDTA(1:1) have little mobilising impact in spite of strong affinity between EDTA and iron. The low affinity between iron and citrate can be compensated by large concentration. Moreover, iron-deficient segments show stronger re-uptake of mobilised 59Fe from the lumen and a stronger transfer of 59Fe from the tissue across the basolateral membrane. Both are compatible with the more marked expression of divalent metal transporter 1 (DMT-1) and IREG-1 at the brushborder and basolateral membrane of iron-deficient enterocytes. The data suggest that iron ions interact with food ligands during their passage from the apical to the basolateral side of duodenal enterocytes.
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http://dx.doi.org/10.1016/j.jtemb.2005.10.005 | DOI Listing |
Blood
July 2023
Food Science and Human Nutrition Department, University of Florida, Gainesville, FL.
Pregnancy rates in β-thalassemia are increasing but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption, and tissue iron overload, with concurrent anemia.
View Article and Find Full Text PDFMetallomics
January 2018
Department of Chemistry and Biochemistry, California State University, Fullerton, CA 92834-6866, USA.
Much evidence indicates that iron stored in ferritin is mobilized through protein degradation in lysosomes, but concerns about this process have lingered, and the mechanistic details of its aspects are lacking. In the studies presented here, Fe-labeled ferritin was induced by preloading hepatic (HepG2) cells with radiolabeled Fe. Placing these cells in a medium containing desferrioxamine resulted in the loss of ferritin-Fe, but adding high concentrations of reducing agents or modulating the internal GSH concentration failed to alter the rates of ferritin-Fe release.
View Article and Find Full Text PDFPLoS One
July 2016
Department of Biochemical Sciences, Charles University in Prague, Faculty of Pharmacy, Hradec Králové, Czech Republic.
Mol Pharmacol
January 2013
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006 Australia.
Deferasirox is an orally effective iron (Fe) chelator currently used for the treatment of iron-overload disease and has been implemented as an alternative to the gold standard chelator, desferrioxamine (DFO). Earlier studies demonstrated that DFO exhibits anticancer activity due to its ability to deplete cancer cells of iron. In this investigation, we examined the in vitro and in vivo activity of deferasirox against cells from human solid tumors.
View Article and Find Full Text PDFJ Med Chem
February 2010
School of Medical Sciences (Pharmacology) and Bosch Institute, University of Sydney, New South Wales 2006, Australia.
Desferrioxamine B (DFOB) conjugates with adamantane-1-carboxylic acid, 3-hydroxyadamantane-1-carboxylic acid, 3,5-dimethyladamantane-1-carboxylic acid, adamantane-1-acetic acid, 4-methylphenoxyacetic acid, 3-hydroxy-2-methyl-4-oxo-1-pyridineacetic acid (N-acetic acid derivative of deferiprone), or 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox) were prepared and the integrity of Fe(III) binding of the compounds was established from electrospray ionization mass spectrometry and RP-HPLC measurements. The extent of intracellular (59)Fe mobilized by the DFOB-3,5-dimethyladamantane-1-carboxylic acid adduct was 3-fold greater than DFOB alone, and the IC(50) value of this adduct was 6- or 15-fold greater than DFOB in two different cell types. The relationship between logP and (59)Fe mobilization for the DFOB conjugates showed that maximal mobilization of intracellular (59)Fe occurred at a logP value approximately 2.
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