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PubMed1988

Characteristics of iron(III) uptake by isolated fragments of rat small intestine in the presence of the hydroxypyrones, maltol and ethyl maltol.

Accumulation of radioactive iron (59Fe) into isolated fragments of rat small intestine in the presence of two hydroxypyrones, maltol and ethyl maltol, was compared with that in the presence of another chelator of iron(III), nitrilotriacetic acid (NTA). The characteristics of uptake were similar with all three ligands. Between 10(-6) and 10(-4) M, iron uptake showed saturable kinetics. The uptake was partially inhibited by metabolic inhibitors. Above 10(-4) M a non-saturable uptake, unaffected by metabolic inhibitors became evident in the presence of the pyrones. The distribution of 59Fe after uptake was determined by gel filtration. At low iron concentrations (10(-6) M), 35-40% of absorbed iron was associated with proteins of molecular weights similar to those of ferritin and transferrin. At high concentrations (10(-3) M), the majority of 59Fe was found in a low molecular weight fraction. At each concentration, a small amount of 59Fe was bound to a membrane fraction. 5% Polyethylene glycol, which reduces glycocalyx viscosity enhanced uptake at low iron concentrations (10(-6) M) but did not affect the non-saturable diffusion seen at higher concentrations (10(-3) M). The iron(II) chelator, bathophenanthroline sulphonate (10(-3) M), decreased uptake at low iron concentrations but did not affect the non-saturable uptake. It is suggested that conversion of iron(III) to iron(II) may take place at the mucosal cell surface before uptake via the saturable system. Apparent Km values for iron uptake via the saturable system were higher in the presence of maltol and ethyl maltol than in the presence of NTA, presumably since the iron binds more avidly to the hydroxypyrones and so is less readily donated. Excess ligand, either pyrone or NTA, reduced the rate at which 59Fe was donated to the uptake system. The Vmax value for uptake from the pyrones was greater than from NTA. It is concluded that maltol, ethyl maltol and NTA can hold iron(III) in solution and donate it to an endogenous uptake system. But, the hydroxypyrones may be more suitable ligands for the oral administration of iron since, when complexed with iron, they lack the toxic effects associated with iron(III)-NTA and with iron(II) preparations.

Animals↗

PubMed1978

Iron absorption in patients with polycythemia vera: a comparative study using the whole-body counter and the ferrous sulfate absorption test.

The absorption of iron given per os to ten polycythemic patients was examined by two methods: first by giving radioactive iron (59Fe) and utilizing a whole-body counter, and second by peroral administration of ferrous sulfate. A correlation of 80% was achieved by the two methods. A comparison was made between the patterns of the ferrous sulfate absorption in the polycythemic patients and in five patients with low iron serum due to bleeding hemorrhoids. No difference was observed between these two groups, with the exception of the initial values which were lower in the polycythemic patients. On the other hand, the absorption of iron was higher in polycythemic patients, indicating that serum iron level is not the only factor regulating iron absorption.

Absorption↗

PubMed1998

Antiproliferative effect of deferiprone on the Hep G2 cell line.

Iron is an essential element in cellular metabolism and the growth of all living species, and is involved in DNA replication. The risk of hepatocellular carcinoma development is associated with an increase in iron availability. The aim of the present work was to investigate the effect of an oral iron chelator, deferiprone (CP20), on HepG2 cell-line proliferation in culture. HepG2 cell cultures were maintained in the absence of fetal calf serum (FCS) and in the presence or not (control cultures) of CP20 at the concentrations of 50 or 100 microM; deferoxamine (DFO) was used as an iron chelator reference. Cell proliferation was investigated by the analysis of DNA synthesis using [3H] methyl-thymidine incorporation and of the cell cycle by flow cytometry. Iron chelation efficiency in the culture model was studied by analyzing the effect of CP20 on radioactive iron uptake, intracellular ferritin level, and transferrin receptor expression. CP20, at the concentration of 50 or 100 microM, inhibited DNA synthesis after 48 hr of incubation and induced an accumulation of the cells in the S phase of the cell cycle. Iron chelators inhibited cellular iron uptake, decreased intracellular ferritin level, and increased transferrin receptor protein and mRNA levels. Our results show that CP20 as well as deferoxamine inhibit HepG2 cell proliferation and block cell cycle in the S phase.

Cell Cycle↗

PubMed1993

Malaria pigment and extracellular iron. Possible target for iron chelating agents.

Extracellular iron is necessary for many biochemical reactions involved in Plasmodium falciparum growth and multiplication. The incorporation of radioactive iron taken up by the parasite was found, electrophoretically and via gamma counting, to be mainly associated with the haemozoin only in the presence of the active metabolism of the parasite. The potent antimalarial activity of desferrioxamine, a ferric iron chelating agent, has shown that iron deprivation is inhibitory to the parasite. We propose that the mechanism of action of desferrioxamine in addition to the chelation of iron from the parasitic compartment, chelates iron from the haemozoin crystal resulting in free radical generation and parasite death. The ability of desferrioxamine and not the ferrous iron chelating agent, 2,2'-bipyridyl, to chelate the non-haem iron from the haemozoin structure indicates that the oxidative state of iron associated with the haemozoin structure is ferric in nature.

2,2'-Dipyridyl↗

PubMed2006

Characterization of ferric and ferrous iron transport systems in Vibrio cholerae.

Vibrio cholerae has multiple iron acquisition systems, including TonB-dependent transport of heme and of the catechol siderophore vibriobactin. Strains defective in both of these systems grow well in laboratory media and in the infant mouse intestine, indicating the presence of additional iron acquisition systems. Previously uncharacterized potential iron transport systems, including a homologue of the ferrous transporter Feo and a periplasmic binding protein-dependent ATP binding cassette (ABC) transport system, termed Fbp, were identified in the V. cholerae genome sequence. Clones encoding either the Feo or the Fbp system exhibited characteristics of iron transporters: both repressed the expression of lacZ cloned under the control of a Fur-regulated promoter in Escherichia coli and also conferred growth on a Shigella flexneri mutant that has a severe defect in iron transport. Two other ABC transporters were also evaluated but were negative by these assays. Transport of radioactive iron by the Feo system into the S. flexneri iron transport mutant was stimulated by the reducing agent ascorbate, consistent with Feo functioning as a ferrous transporter. Conversely, ascorbate inhibited transport by the Fbp system, suggesting that it transports ferric iron. The growth of V. cholerae strains carrying mutations in one or more of the potential iron transport genes indicated that both Feo and Fbp contribute to iron acquisition. However, a mutant defective in the vibriobactin, Fbp, and Feo systems was not attenuated in a suckling mouse model, suggesting that at least one other iron transport system can be used in vivo.

ATP-Binding Cassette Transporters↗

PubMed1989

Vitellogenin-iron and hemoglobin synthesis in avian reticulocytes.

Avian vitellogenin has been studied as an iron carrier for hemoglobin synthesis by reticulocytes. The Fe-vitellogenin uptake by the immature red cells is progressive with time, following an unspecific iron uptake process. The iron uptake from Fe-vitellogenin was in proportion to the immature red cells present and the radioactive iron was found in the hemoglobin synthesized by these cells. These results open up the possibility of assigning a secondary role to the Fe-vitellogenin in the avian erythropoiesis, added to the classical iron transport function for egg production.

Animals↗

PubMedDate not supplied

Intravenous infusion pharmacokinetics of desferrioxamine in thalassaemic patients.

Pharmacokinetic investigation of desferrioxamine (DFO) was conducted in 11 thalassaemic patients following continuous intravenous infusion of 50 mg/kg/24 hr over 48 hr. Serial venous blood samples were obtained at regular time intervals during and on stopping DFO infusion. Plasma samples were processed with the addition of radioactive iron (59Fe) to stabilize free ligand forms of DFO and its metabolites. This resulted in the formation of both radioactive and nonradioactive forms of ferrioxamine and its metabolites. Following solid-phase extraction, plasma samples were analyzed by a reversed-phase HPLC and monitored by simultaneous UV-visible radioactive detection. DFO was found to be eliminated from the blood in a biexponential manner with a systemic clearance of 0.50 +/- 0.24 liters/hr/kg. The terminal half-life was 3.05 +/- 1.30 hr, and the volume of distribution was 1.88 +/- 1.0 liters/kg at the terminal phase and 1.35 +/- 0.65 liters/kg at steady state. The AUC of DFO was 354 +/- 131 mumol/liter.hr. The major metabolite of DFO, DFO-metabolite B, has an initial half-life of 1.33 +/- 0.61 hr and is usually present at lower concentrations relative to the parent compound with an AUC of 191 +/- 106 mumol/liter.hr.

Chromatography, High Pressure Liquid↗

PubMed1953

An analytical study of in vivo survival of limited populations of animal red blood cells tagged with radio-iron.

Animal red blood cell in vivo survival curves, obtained by the radioiron tagging of populations of approximately the same age followed by the administration of non-radioactive iron to suppress radioiron reutilization, have been subjected to mathematical analysis on the basis of the three following assumptions:- (A) Red blood cells disappear from the circulation as the result of senescence: there is an average life span around which the life spans of individual cells are distributed in the usual way. (B) Red blood cells may be removed from the circulation by a process of random destruction which continuously removes a constant fraction of the cells present at any moment irrespective of age or other characteristics. (C) Under the conditions of the experiments described, a fraction of the radioiron, constant for each animal, is reutilized in new red cell formation when released by red cell destruction. This mathematical analysis indicates the following average life spans with the respective standard errors of the mean: dog 107 days +/- 1.14; rabbit 67.6 days +/- 1.94; cat 68.4 +/- 1.50. The mathematical treatment presented has permitted a consideration of the theoretical variation of red cell life spans which was found in these experiments to be relatively small for all three species studied. In the rabbit and cat 2.5 per cent of tagged populations of red cells of the same age would theoretically have disappeared by senescence 17 days before the average life span was reached. The variation of red cell life in the dog was slightly less. Animals of the three species studied, in spite of apparently normal health, exhibited varying degrees of random destruction of both autogenous and transfused fresh normal homologous red cells. As yet, we have no explanation for this random loss of cells occurring in apparently healthy normal animals. The method of mathematical analysis presented is applicable to animal red cell survival studies employing radioiron in which differing rates of random destruction are operating in the removal of red cells.

Animals↗

PubMed1975

Effect of milk and casein on the absorption of supplemental iron in the mouse and chick.

Milk is an attractive vehicle for introducing iron supplements into iron-deficient infants and children. This study compares the effects of milk and caseins on the whole-body absorption of radioactive iron complexes in an attempt to resolve the controversy over whether milk and its constituent phosphoproteins seriously impair iron absorption. Evidence is presented to clarify the role of the calcium-casein micelles of cow's milk in binding iron donated by the ferric-nitrilotriacetate (NTA) complex. The absorption of iron from isolated Fe(III)-casein complexes was studied in mice as a function of the casein--to--Fe ratio and was compared with the absorption of Fe(III)-NTA at equivalent levels. Even at casein--to--Fe ratios higher than those found in conventional iron-supplemented cow's milk (10-15 mg Fe/qt; casein P:Fe congruent to 34), absorption of iron(III) from the casein or NTA complex was not significantly different. There was no significant difference in the absorption of iron administered to mice and chicks as ferrous ion, ferric-NTA, or ferric fructose; nonfat cow's milk did not inhibit the absorption of these iron compounds. For the chick, in fact, milk significantly enhanced the absorption of iron from the ferric-NTA chelate. In order to affect iron absorption significantly casein would have to be present considerably in excess of that found in conventionally supplemented cow's milk.

Absorption↗

PubMed1982

Hepatocyte iron kinetics in the rat explored with an iron chelator.

The hepatocyte metabolism of 59Fe-labelled ferritin, haemoglobin-haptoglobin and transferrin has been examined in rats. All three forms of 59Fe became transiently available to desferrioxamine (DF) at the time they would otherwise have entered storage or alternative pathways of iron metabolism. However, differences in both the patterns of spontaneous 59Fe reutilization by normal and iron deficient rats and the partition of chelate iron excretion between bile and urine, suggested that iron in transit within hepatocytes did not behave as a single common pool. Ferritin 59Fe, entering a pool of non-radioactive iron the size of which is determined by liver iron stores, was chelated predominantly into the bile. Transferrin 59Fe was distinguished by a greater reflux to the erythron in iron deficient rats, and by excretion of a larger proportion of 59Fe chelated by DF in the urine. Haemoglobin-haptoglobin 59Fe followed a metabolic pathway which was relatively independent of both the iron stores and DF. If the heterogeneous behaviour of rat hepatocyte transit iron has a parallel in man, alterations in the size of similar chelatable iron pools could explain the dependence of DF-induced urine and faecal iron excretion on both liver iron stores and the level of erythropoiesis.

Animals↗

PubMed1979

Quantitation of erythropoiesis in myelomatosis.

Quantitation of the erythropoiesis with radio-iron (59Fe) was applied to 9 patients with untreated myelomatosis. The method included blocking of the 59Fe reutilization by injection of non-radioactive iron. There was no uniform pattern in the Fe-kinetics values. The Plasma Iron Turnover (PIT) and the Red Blood Cell Iron Turnover (RBCIT) varied from subnormal to values markedly increased above upper normal limit. The calculated average Mean Red Cell Life time (MRCL) of erythrocytes was just below normal range. The mean Marrow Transit Time (MTT) was normal in the patients, despite subnormal venous haematocrit, indicating insufficient stimulation of the bone marrow. The renal function, measured as 51Cr-EDTA clearance, was found positively correlated to the RBCIT (r = 0.78, P less than 0.05). The results suggest that the previously demonstrated relationship between anaemia and renal failure in patients with myelomatosis is caused mainly by an inability of the bone marrow to produce sufficient red blood cells under the stress of anaemia related to the degree of renal impairment.

Aged↗

PubMed1977

Sideroblastic anemia in an elderly patient.

A 91-year-old man had been treated for iron-deficiency anemia for four years before admission to the Geriatric Unit of the Hasharon Hospital because of cardiac insufficiency and epigastric pain. In the Unit, laboratory studies revealed, in addition to hypochromic anemia, a high level of plasma iron and a reduced iron-binding capacity. The low reticulocyte count in the peripheral blood despite hyperplasia in the bone-marrow erythrocyte series, the rapid disappearance of radioactive iron from the plasma, and the impaired erythrocytic uptake of iron were all indicative of the ineffective erythropoiesis. The findings suggested the possibility of sideroblastic anemia, and examination of bone-marrow aspirates stained for iron confirmed this diagnosis.

Aged↗

PubMed1984

[Effect of iron on Pasteurella multocida].

Iron is an important factor for growth, virulence and immunogenicity of the species Pasteurella multocida. This has been demonstrated in numerous experiments with bacterial cultures in vitro and immunized and not immunized animals in vivo (mice, piglets, calves). Iron substrates or iron chelators affect in different manner the virulence of P. multocida in vivo, depending on chemical character of the given compounds, their dose, route and time of application, and also depending on the host. P. multocida has an up to time unknown iron transport system, which can acquire the essential iron from physiological substances, such as heme, ferritine, transferrine, lactoferrine etc. This conclusion results from in vitro experiments with growing cultures, with insertion of radioactive iron (Fe-59) from different sources, and with iron solubilization in neutral pH ranges. In the same way, the iron of iron dextran and low molecular iron compounds is available for P. multocida. Iron of unphysiological complexes, potassium ferrocyanide, and ferrocene is unavailable. On the other side such iron chelating agents as nitrilotriacetate, tirone, ferrocene, citrate, EDTA, and apotransferrine do not or only a little affect growth, and such chelators as alpha, alpha'-dipyridyle, phenanthroline and the microbial siderophores deferrioxamin B and enterobactin are inhibitory substances for multiplication of P. multocida. This substances also inhibit the insertion of Fe-59 into the bacterial cell. The conclusion is drawn that neither enterobactin nor deferrioxamine B as typical representatives of phenolate or hydroxamate siderophores take part in Fe-transport of P. multocida.

Animals↗

PubMed1997

Transport of iron in the blood-brain-cerebrospinal fluid system.

Iron is an important constituent in brain and, in certain regions, e.g., the basal nuclei, reaches concentrations equivalent to those in liver. It has a role in electron transfer and is a cofactor for certain enzymes, including those involved in catecholamine and myelin synthesis. Iron in CSF is likely to be representative of that in interstitial fluid of brain. Transferrin in CSF is fully saturated, and the excess iron may be loosely bound as Fe(II). Brain iron is regulated in iron depletion, suggesting a role for the blood-brain barrier (BBB). Iron crosses the luminal membrane of the capillary endothelium by receptor-mediated endocytosis of ferric transferrin. This results in an initial linear uptake of radioactive iron into brain at an average rate relative to serum of about 3.3 x 10(-3) ml x g of brain(-1) x h(-1) in the adult rat. This corresponds to about 80 nmol x kg(-1) x h(-1). Much higher rates occur in the postnatal rat. These increase during the first 15 days of life and decline thereafter. Within the endothelium, most of the iron is separated from transferrin, presumably by the general mechanism of acidification within the endosome. Iron appears to be absorbed from the vesicular system into cytoplasm and transported across the abluminal plasma membrane into interstitial fluid as one or more species of low molecular weight. There is some evidence that ionic Fe(II) is involved. Certainly Fe(II) ions presented on the luminal side rapidly cross the complete BBB, i.e., luminal and abluminal membranes. Within interstitial fluid, transported iron will bind with any unsaturated transferrin synthesized or transported into the brain-CSF system. Oligodendrocytes are one site of synthesis. From interstitial fluid, ferric transferrin is taken up by neurones and glial cells by the usual receptor-mediated endocytosis. Calculations of the amount of iron leaving the system with the bulk flow of CSF indicate that most iron entering brain across the capillary endothelium finally leaves the system with the bulk outflow of CSF through arachnoid villi and other channels. A system in which influx of iron into brain is by regulated receptor-mediated transport and in which efflux is by bulk flow is ideal for homeostasis of brain iron.

Animals↗

PubMed2001

Iron and zinc bioavailability in rats fed intrinsically labeled bean and bean-rice infant weaning food products.

Beans are the core of the Latin American diet and contain iron and zinc. However, the bioavailability of these trace minerals from beans is low. The objective of this study was to determine if the bioavailability of iron and zinc could be improved with the use of fermentation and germination processing technologies. Black beans native to Costa Rica were grown hydroponically with either radioactive iron or zinc. The influence of fermentation and germination on iron and zinc bioavailability from intrinsically labeled infant weaning food products based on black beans and beans-rice was determined in rats. Mineral bioavailability was determined using whole-body (59)Fe retention for iron, and whole-body (65)Zn retention and incorporation of radiolabel into bone for zinc. Percent absorption of (59)Fe from fermented products ranged between 48.0 and 58.0. Percent absorption of (65)Zn ranged from 57.0 to 64.0. Fermentation did not increase iron bioavailability in rats fed fermented beans without rice. Fermentation of cooked beans significantly increased zinc retention. Germination significantly enhanced iron retention from cooked beans from 46 to 55% and from cooked beans-cooked rice from 34 to 48%. Germination significantly improved zinc absorption and retention from cooked beans without added rice.

Absorption↗

PubMed1980

Hydroxamate-mediated transport of iron controlled by ColV plasmids.

A new high-affinity system for iron transport, associated with the presence of ColV plasmids, has been detected in Escherichia coli and partially characterized. The presence of such "iron-transport plasmids" in E. coli cells that are defective in enterochelin-mediated transport of iron enabled them to grow in media to which 2,2'-dipyridyl had been added to reduce availability of iron. In addition, the presence of plasmid deoxyribonucleic acid in a mutant defective in enterochelin biosynthesis was associated with a marked increase in the rate of radioactive-iron uptake. Plasmid-determined uptake of iron was distinct from previously recognized systems for iron transport in E. coli K-12, and the colicin V molecule appeared not to be directly involved. Hydroxylamine-nitrogen could be detected in cell pellets of ColV+ cultures, and similar material was detected in supernatant fluids of late log- or stationary-phase cultures. The hydroxamate material was not detected in cell pellets or culture supernatants of strains from which plasmids had been eliminated, and a 95% decrease in hydroxamate synthesis was observed when cells were grown in minimal medium containing 2 microM iron.

Biological Transport, Active↗

PubMed2001

Exploring the "iron shuttle" hypothesis in chelation therapy: effects of combined deferoxamine and deferiprone treatment in hypertransfused rats with labeled iron stores and in iron-loaded rat heart cells in culture.

Although iron chelation therapy results in a significant improvement in well-being and life expectancy of thalassemic patients with transfusional iron overload, failure to achieve these goals in a substantial proportion of patients underlines the need for improved methods of treatment. In the present studies we used selective radioactive iron probes of hepatocellular and reticuloendothelial (RE) iron stores in hypertransfused rats and iron-loaded heart cells to compare the source of iron chelated in vivo by deferoxamine (DFO) or by deferiprone (L1) and its mode of excretion, to examine the ability of DFO and L1 to remove iron directly from iron-loaded myocardial cells, and to examine the mechanism of their combined interaction through a possible additive or synergistic effect. Our results indicate that L1 given orally is 1.6 to 1.9 times more effective in rats, on a weight-per-weight basis, than parenteral DFO in promoting the excretion of storage iron from parenchymal iron stores but shows no advantage over DFO in promoting RE iron excretion. Simultaneous administration of DFO and L1 results in an increase in chelating effect that is additive but not synergistic. The magnitude of this additive effect is identical to an increase in the equivalent (weight or molar) dose of DFO alone rather than the sum of the separate effects of L1 and DFO. This finding is most probably the result of a transfer of chelated iron from L1 to DFO. These observations may have practical implications for current efforts to design better therapeutic strategies for the management of transfusional iron overload.

Animals↗

PubMed1987

Modification of iron uptake and lipid peroxidation by hypoxia, ascorbic acid, and alpha-tocopherol in iron-loaded rat myocardial cell cultures.

The ability of ascorbic acid, alpha-tocopherol, and hypoxia to modify iron uptake, chelation, and toxicity as manifested by the generation of malonyldialdehyde (MDA) was studied in myocardial cell cultures obtained from newborn rats. Exposure to 20 micrograms/ml iron provided as 59Fe-ferric ammonium citrate in serum-free Ham F-10 culture medium resulted in the accumulation of 39% of the iron within 24 hours and a 10- to 12-fold increase in cellular MDA. Hypoxia (1% oxygen) resulted in a more than twofold increase in iron uptake but only minor changes in cellular MDA concentrations. Ascorbic acid and alpha-tocopherol (1 mg/ml) had opposing effects on iron uptake and MDA production. Ascorbic acid reduced 24-hour iron uptake by 73% (P less than 0.001) whereas alpha-tocopherol increased iron uptake by 19% (P less than 0.025). In contrast, cellular MDA after iron loading increased by 86% with the addition of ascorbate, and was reduced by 75% with alpha-tocopherol (P less than 0.001). The ratio of increase in cellular MDA relative to percent iron uptake (lipid peroxidation ratio) was 7.29 with iron loading plus ascorbate vs. 0.13 with iron loading plus alpha-tocopherol, a 56-fold difference between the two extremes. In vitro deferoxamine treatment for 3 hours resulted in a 53% reduction in the radioactive iron content of iron-loaded heart cells and a 40% reduction in MDA. Simultaneous deferoxamine and ascorbate or alpha-tocopherol treatment did not affect iron mobilization, but had a profound effect on MDA concentrations. Ascorbic acid prevented entirely the beneficial effect of deferoxamine on MDA concentrations in iron-loaded cells, whereas alpha-tocopherol potentiated the effect of deferoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗