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PubMed1981

Effects of maternal iron nutrition during lactation on milk iron and rat neonatal iron status.

We studied the milk iron content and iron status of lactating rats and their pups to investigate the relationships between the iron concentrations of maternal diet and the iron content of milk, and that between the milk iron content and neonatal iron status. Three days after parturition lactating rats were divided into three groups and fed a control (250 ppm iron), a high iron (2500 ppm iron), and an iron-deficient (no iron) diet. During lactation pups and dams from each group were killed periodically and iron status determined by measurements of hemoglobin, plasma iron, total iron binding capacity, and ferritin. Milk iron concentration decreased in all diet groups during lactation. The rate of decrease was diet dependent. A definite relationship was seen between the milk iron content of dams and the iron status of their pups. The iron concentration of rat diet was also found to influence the maternal iron during lactation.

Animals↗
PubMed2002

Labile iron in parenteral iron formulations and its potential for generating plasma nontransferrin-bound iron in dialysis patients.

BACKGROUND: Labile plasma iron (LPI) associated with iron supplementation has been implicated in complications found in dialysis patients. As LPI can potentially catalyse oxygen radical generation, we determined the presence of labile iron in the parenteral preparations and the frequency of occurrence of LPI in dialysis patients. DESIGN: The capacity to donate iron to apotransferrin (apo-) or to the chelator desferrioxamine (DFO) was measured with fluorescein-Tf (Fl-Tf) and Fl-DFO, respectively. Those probes undergo quenching upon binding to iron. Iron-catalysed generation of oxidant species was determined with dihydrorhodamine. Plasma nontransferrin-bound iron (NTBI), here termed LPI, was determined by mobilization of iron from low-affinity binding sites with oxalate, followed by its quantification with Fl-Tf in the presence of Ga(III). RESULTS: Normal individuals and most (80%) dialysis patients, analysed at least 1 week after iron supplementation showed no detectable (<0.2 microm) LPI. However, approximately 20% of the patients (n = 71) showed significant LPI levels (>0.2 microm), in some cases weeks after iron administration. LPI levels correlated best (r2 = 0.9) with Tf saturation. The iron preparations contained 2-6% low molecular weight and redox-active iron, most of which is chelated by Tf. CONCLUSIONS: Parenteral iron formulations contain a small but significant fraction of redox-active iron, most of which is scavenged by apo-Tf within <1 h. Therefore, oxidant stress associated with iron infusion is likely to be transient. The bulk of the polymeric iron is apparently inaccessible to apo-Tf. Although LPI might return to normal within 2 h of intravenous iron infusion, the long-term persistence of low-level LPI in up to 20% of end stage renal disease (ESRD) patients indicates that complete clearance of the intravenous iron may be more protracted than originally estimated.

Adolescent↗
PubMed1994

Iron acquisition and expression of iron regulatory proteins in the developing brain: manipulation by ethanol exposure, iron deprivation and cellular dysfunction.

The World Health Organization considers iron deficiency the number one nutritional disorder in the world. In this review, the normal pattern for iron accumulation and expression of iron regulatory proteins (transferrin and its receptor, and ferritin) in brain during development are examined biochemically and at the cellular and molecular levels. Iron and the iron-regulatory proteins are at their highest postnatal concentration in the brain at birth, decline over the preweaning period and then increase to adult levels. Evidence is presented that in utero exposure to alcohol, iron-deficient diets, and dysfunctional oligodendrocytes can influence the normal pattern for iron accumulation in the brain which sets off a cascade of events that results in loss of regulatory control of iron. Because iron is an essential cofactor in neurotransmitter synthesis and myelination altering iron availability during vulnerable periods of development may have a permanent influence both on iron homeostasis in the brain and motor and cognitive function. At the cellular level, iron-positive cells in the subventricular zone and myelinogenic foci are present as early as postnatal day 3. Disruption of oligodendrocyte maturation is associated with altered expression and cellular accumulation of iron, transferrin and the transferrin receptor in brain. These data indicate that iron delivered via transferrin and its receptor is intrinsically involved in oligodendrocyte maturation and thus plays a critical role in the onset of myelination. In the adult, oligodendrocytes are the predominant iron-regulatory cell in the brain by virtue of their high content of iron, transferrin and ferritin. From these studies we conclude oligodendrocytes may be responsible for iron regulation in the brain at the cellular level and that brain iron regulatory mechanisms are vulnerable to manipulation during postnatal development.

Animals↗
PubMed1988

Accumulation of iron and iron compounds in liver tissue. A comparative study of the histological and chemical estimation of liver iron.

Unsatisfactory results obtained by histological evaluation of liver tissue in iron loading diseases prompted us to study the distribution of the total liver iron, haem iron and ferritin iron in post mortem human liver tissue from two different sites of the same liver. The total liver iron content was measured by flameless atomic absorption spectroscopy in native liver homogenates and in acid digested liver tissue from 60 consecutive autopsies, and the results from the two methods were compared. From the standard deviation of the duplicate analyses, it was deduced that the liver iron is possibly inhomogeneously distributed. The CVduplo (22%) of total iron, measured in acid digested tissue was higher than the CVduplo (14%) of total iron in homogenates from liver tissue from which non-homogenized tissue e.g. vessel walls, fibrotic tissue, had been removed. The CVduplo of ferritin iron and haem iron in liver homogenate was 14% and 30% respectively. The ferritin iron increased with an increasing total iron content until saturation of ferritin iron appeared to be reached at 2.5 micrograms ferritin iron per mg liver protein. When the results of total non-heam liver iron measurements are expressed properly (amount of iron per amount of homogenized liver protein), the distribution of iron is found to be homogeneous in both normal and pathological liver tissues. It was concluded that the estimation of liver iron content by visual microscopic evaluation is unsatisfactory, and that more reliable results are obtained by atomic absorption spectrophotometry.

Ferric Compounds↗
PubMed2001

Effect of iron deficiency on placental transfer of iron and expression of iron transport proteins in vivo and in vitro.

Maternal iron deficiency during pregnancy induces anaemia in the developing fetus; however, the severity tends to be less than in the mother. The mechanism underlying this resistance has not been determined. We have measured placental expression of proteins involved in iron transfer in pregnant rats given diets with decreasing levels of iron and examined the effect of iron deficiency on iron transfer across BeWo cell layers, a model for placental iron transfer. Transferrin receptor expression was increased at both mRNA and protein levels. Similarly, expression of the iron-responsive element (IRE)-regulated form of the divalent metal transporter 1 (DMT1) was also increased. In contrast, the non-IRE regulated isoform showed no change in mRNA levels. Protein levels of DMT1 increased significantly. Iron efflux is thought to be mediated by the metal transporter protein, IREG1/ferroportin1/MTP1, and oxidation of Fe(II) to Fe(III) prior to incorporation into fetal transferrin is carried out by the placental copper oxidase. Expression of IREG1 was not altered by iron deficiency, whereas copper oxidase activity was increased. In BeWo cells made iron deficient by treatment with desferrioxamine ('deferioxamine'), iron accumulation from iron-transferrin increased, in parallel with increased expression of the transferrin receptor. At the same time, iron efflux also increased, showing a higher flux of iron from the apical to the basolateral side. The data show that expression of placental proteins of iron transport are up-regulated in maternal iron deficiency, resulting in an increased efficiency of iron flux and a consequent minimization of the severity of fetal anaemia.

Anemia, Iron-Deficiency↗
PubMed2005

Iron prophylaxis during pregnancy -- how much iron is needed? A randomized dose- response study of 20-80 mg ferrous iron daily in pregnant women.

OBJECTIVE: To determine the lowest dose of iron preventative of iron deficiency and iron deficiency anemia in pregnancy. METHODS: A randomized, double-blind intention-to-treat study comprising 427 healthy pregnant women allocated into four groups taking ferrous iron (as fumarate) in doses of 20 mg (n = 105), 40 mg (n = 108), 60 mg (n = 106), and 80 mg (n = 108) from 18 weeks of gestation. Iron status markers [hemoglobin (Hb), serum ferritin, and serum soluble transferrin receptor (sTfR)] were measured at 18 weeks (inclusion), 32 weeks, and 39 weeks of gestation and 8 weeks postpartum. Side effects of iron supplements were recorded. Iron deficiency was defined as serum ferritin <13 microg/l and iron deficiency anemia as serum ferritin <13 microg/l and Hb <5th percentile in iron replete pregnant women. RESULTS: There were no significant differences between variables in the four groups at inclusion. At 32 and 39 weeks of gestation, group 20 mg had significantly lower median serum ferritin (13 and 16 microg/l) than group 40 mg (17 and 21 microg/l), group 60 mg (18 and 23 microg/l), and group 80 mg (21 and 24 microg/l) (p < 0.0001). At 32 and 39 weeks of gestation, group 20 mg had a significantly higher prevalence of iron deficiency (50 and 29%) than group 40 mg (26 and 11%), group 60 mg (17 and 10%), and group 80 mg (13 and 9%) (p < 0.001). The prevalence of iron deficiency anemia at 39 weeks of gestation was significantly higher in group 20 mg (10%) than in group 40 mg (4.5%), group 60 mg (0%), and group 80 mg (1.5%) (p = 0.02). At 32 weeks of gestation, mean Hb in group 20 mg was lower than in group 80 mg (p = 0.06). There were no significant differences in iron status (ferritin, sTfR, and Hb) between group 40, 60, and 80 mg. Postpartum, group 20 mg had significantly lower median serum ferritin than group 40, 60, and 80 mg (p < 0.01). The prevalence of postpartum iron deficiency anemia was low and similar in the four groups. The frequency of gastrointestinal symptoms was not significantly different in the four iron supplement groups and thus not related to the iron dose. CONCLUSION: In Danish women, a supplement of 40 mg ferrous iron/day from 18 weeks of gestation appears adequate to prevent iron deficiency in 90% of the women and iron deficiency anemia in at least 95% of the women during pregnancy and postpartum.

Adult↗
PubMed2003

Iron-activated iron uptake: a positive feedback loop mediated by iron regulatory protein 1.

The love-hate relationship between iron and living matter has generated mechanisms to maintain iron concentration in a narrow range, above and below which deleterious effects occur. At the cellular level, iron homeostasis is accomplished by the activity of the IRP proteins, which, under conditions of iron depletion, up-regulate the expression of the iron acquisition proteins TfR and DMT1. It has been shown that hydrogen peroxide activates IRP1 and that this activation mediates a potentially harmful increase in cell iron uptake. Here we show that IRP1 activity is also induced by iron-mediated oxidative stress. When cells were incubated with up to 20 microM of iron, a typical decrease in IRP1 and IRP2 activity was observed. Interestingly, when iron was further increased to 40 or 80 microM. IRP1 was reactivated in three of the four different cell lines tested, i.e., Caco-2 cells, N2A cells and HepG2 cells. In the fourth cell line (K562) IRP1 activity did not increase, but neither did it decrease. This response to iron was largely abrogated when the antioxidant N-acetyl cysteine was added along with iron to the culture medium. Thus, the effect of iron was mediated by oxidative stress. Increases in IRP1 activity were accompanied by increases in cell iron uptake, an indication that the activated IRP1 was functional in the activation of iron uptake. Hence, this iron-induced iron uptake feedback loop results in the increase of intracellular iron and increased oxidative stress.

Analysis of Variance↗
PubMed1997

Regional brain iron, ferritin and transferrin concentrations during iron deficiency and iron repletion in developing rats.

Iron deficiency in young rats leads to a decrease in brain iron and ferritin concentrations, an increase in transferrin (Tf) concentration, and an increased rate of uptake of iron from the plasma pool. We conducted two experiments to determine whether brain iron, Tf and ferritin respond quickly to iron repletion and to determine whether brain regions respond heterogeneously. Weanling male Sprague-Dawley rats were fed an iron-deficient diet (<5 mg/kg Fe) for 2 wk followed by an iron-adequate diet (REPL group, 35 mg/kg Fe in Experiment 1 and 15 mg/kg Fe in Experiment 2) for 2 or 4 wks, respectively. Age-matched iron-deficient (ID) and control rats composed the other two groups. Fourteen days of repletion with 35 mg/kg Fe dietary treatment were adequate to normalize hematology, brain microsomal and cytosolic Fe and brain ferritin (Experiment 1). Brain transferrin concentrations in REPL rats, however, were significantly above the levels of controls. Regional brain iron decreased heterogeneously due to dietary iron deficiency (Experiment 2), with some regions having a propensity to keep iron (e.g., substantia nigra, pons, and thalamus) and others losing significant amounts of iron (cortex and hippocampus). Ferritin and Tf concentrations also varied significantly across brain regions in ID and control rats. The hippocampus had the most dramatic Tf response to iron deficiency with elevations of approximately 100%, whereas other regions, except striatum, were unaffected. The brain of developing rats thus distributes iron and iron regulatory proteins differently from the brain of adult rats and is quite avid in its reacquisition of iron during iron therapy.

Anemia, Iron-Deficiency↗
PubMed1997

Iron supplementation in pregnancy: is less enough? A randomized, placebo controlled trial of low dose iron supplementation with and without heme iron.

BACKGROUND: The purpose of the present study was to evaluate the efficacy of low dose iron supplementation with and without a heme component, prescribed for women in the second half of pregnancy. METHOD: A randomized, double-blind, placebo controlled trial. Thirty-one women received a daily dose of 27 mg elemental iron in a product containing both heme iron and non-heme iron (Hemofer), 30 women received the same dose as pure non-heme iron with vitamin C (Collets jern med vitamin C), and 29 women received placebo. A double dummy technique was used to mask tablets. The women were tested for red cell indices and iron status markers (s-ferritin, s-iron, Total Iron Binding Capacity and erythrocyte protoporphyrin) throughout pregnancy and 8 and 24 weeks postpartum. The results were analyzed according to the 'intention to treat' principle. RESULTS: The hematological effects were equal in the two treatment groups. 25% of the supplemented women fell below 110 g/l in Hb vs 52% in the placebo group (p < 0.05); none fell below 100 g/l in the supplemented groups, 14% in the placebo group. Iron status was significantly better for all measured parameters in the heme iron group compared to placebo at the end of pregnancy. Differences between the other groups were only shown for some parameters, probably due to the small sample size. In the heme iron group there were fewer women with empty iron stores postpartum than at the start of pregnancy (from 14% to 8%), in the non-heme iron group there was a significant increase (from 3% to 27%), and in the placebo group the percentage of women with empty iron stores was more than doubled (from 21% to 52%). CONCLUSIONS: A daily dose of 27 mg elemental iron, containing a heme component, given in the second half of pregnancy, prevents depletion of iron stores after birth in most women. An equivalent dose of pure inorganic iron seems less effective, but the sample size in this study was too small to demonstrate significant differences between the two treatment groups.

Anemia, Iron-Deficiency↗
PubMed2002

The effect of different iron fortificants on iron absorption from iron-fortified rice.

Iron absorption from rice fortified with different iron fortificants, e.g., ferrous sulfate (FeS04), sodium iron EDTA (NaFeEDTA), ferrous fumarate (FeFum), and ferrous bisglycinate (FeBis) was determined using an in vitro enzymatic digestion method simulating conditions in the small intestine and an in vivo method using radioisotope techniques. The in vitro method showed that the percentage of dialyzable iron from NaFeEDTA (15.7 +/- 0.9) and FeS04-fortified rice (13.2 +/- 1.5) was significantly greater than that from FeFum (6.4 +/- 0.6; p < .05) and FeBis fortified rice (3.3 +/- 0.8; p < .05). Iron absorption in vivo was investigated from FeS04 and NaFeEDTA fortified rice with and without fish and vegetables in 10 borderline iron-deficient subjects. Iron absorption (mg) from NaFeEDTA fortified rice (0.44 +/- 0.11) was significantly greater than from FeS04-fortified rice (0.22 +/- 0.05; p < .05) and the unfortified rice (0.17 +/- 0.02; p < .05). Iron absorption (mg) from a meal consisting of iron-fortified rice, fish, and vegetables was significantly greater from NaFeEDTA (0.88 +/- 0.24) and FeS04 (0.67 +/- 0.10) -fortified rice than from the unfortified rice (0.41 +/- 0.08; p < .05). This study concluded that both NaFeEDTA and FeSO4 are effective iron fortificants for rice. The binder used in the study may have a significant role in the release of iron from iron-fortified rice for absorption. Further studies on the use of other binders to maximize iron release and minimize iron loss during cooking should be conducted to improve iron absorption from the fortified rice/rice-fish-vegetable meals. Results from this study can be used as a basis for food iron fortification programs as well as in the establishment of recommended dietary allowances for iron among Filipinos.

Adult↗
PubMed1994

Iron-balance and dose-response studies of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in iron-loaded patients with sickle cell disease.

Several life-threatening complications of the common disorder sickle cell disease require management with red blood cell transfusions and, hence, long-term iron-chelating therapy. The efficacy of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) has not previously been determined in patients with sickle cell disease. We compared the efficacy of L1 to that of standard-dose subcutaneous deferoxamine in four regularly transfused patients with homozygous sickle cell disease, who had evidence of severe iron overload and a history of poor compliance with deferoxamine. Determination of 24-hour urinary iron excretion conducted over 5 days immediately after transfusion showed that the mean daily urinary iron excretion induced by L1 at 75 mg/kg/d (0.48 +/- 0.23 mg/kg) was equivalent to that induced by deferoxamine at 50 mg/kg/d (0.39 +/- 0.06 mg/kg). In two of three patients studied, a significant (P < .025) increase in mean daily urinary iron excretion was achieved when the dose of L1 was increased to 100 mg/kg/d. Total iron balance studies, which quantitated both urinary and stool iron excretion on L1 and deferoxamine, determined that mean total daily iron excretion induced by deferoxamine (0.88 +/- 0.05 mg/kg) was significantly greater (P < .05) than that induced by L1 (0.53 +/- 0.17 mg/kg), attributable to the significantly greater stool iron excretion during deferoxamine treatment (0.50 +/- 0.16 mg/kg/d) compared with that measured during L1 treatment (0.12 +/- 0.08 mg/kg/d, P < .01). Stool iron excretion accounted for a significantly greater percentage of total iron excretion during deferoxamine treatment (59% +/- 20%) than during L1 treatment (23% +/- 14%, P < .01). These iron balance studies are the first to compare total iron excretion induced by L1 with that achieved by deferoxamine. They demonstrate that the mean total daily iron excretion during L1 treatment (0.53 +/- 0.17 mg/kg) is sufficient to maintain net negative iron balance in most regularly transfused patients with sickle cell disease. Because long-term compliance with L1 has been shown previously to be superior to that with deferoxamine in patients with homozygous beta-thalassemia, the use of L1 should increase the long-term effectiveness of iron chelation in patients with sickle cell disease.

Administration, Oral↗
PubMed1999

Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa. Possible implications for the regulation of iron absorption.

Duodenal enterocytes adjust intestinal iron absorption to the body's state of iron repletion. Here we tested how iron supply from the blood modulates the RNA-binding activity of iron regulatory proteins (IRP-1 and IRP-2) in immature duodenal rat enterocytes, and whether the modulation is compatible with the hypothesis that IRPs, in turn, may regulate the expression of iron transport proteins in maturating enterocytes during migration to the villus tips. Tissue uptake of parenterally applied 59Fe along the duodenal crypt-villus axis was compared to local IRP-1 and IRP-2 activity and to duodenal 59Fe transport capacity 12 h, 48 h, and 72 h after intravenous iron administration to iron-deficient rats. IRP-1 and IRP-2 activity was significantly increased in iron-deficiency. 59Fe administrated from the blood side was almost exclusively taken up by crypt enterocytes. Accordingly, the activity of IRP-1 decreased at this site 12 h after parenteral iron administration, but remained high at the villus tips. After 48 h the bulk of 59Fe containing enterocytes had migrated to the villus tips. Correspondingly, IRP-1 activity was decreased at duodenal villus tips after 48 h. IRP-2 activity also tended to decrease, though the change was statistically not significant. IRP-2 activity remained significantly higher at duodenal villus tips than in crypts, even after 72 h. Intestinal iron absorption capacity decreased with the same delay as IRP-1 activity after intravenous iron administration. In the ileum 59Fe uptake from the blood and IRP activity showed no significant difference between crypt and villus region. Luminal administration of iron decreased duodenal IRP-1 and IRP-2 activity at tips and crypts within 2 h. Thus, recently absorbed iron becomes available to cytosolic IRP during its passage through the enterocyte. Our results are compatible with a role of IRPs in gearing the expression of intestinal iron transporters in the duodenal brushborder to the body's state of iron repletion.

Absorption↗
PubMed1992

Deferoxamine-induced iron mobilization and redistribution of myocardial iron in cultured rat heart cells: studies of the chelatable iron pool by electron microscopy and Mössbauer spectroscopy.

Iron mobilization by deferoxamine from iron-loaded rat heart cells in culture was studied by electron microscopy and Mössbauer spectroscopy to identify the chelatable iron pool. Studies in which iron 59 was used have shown a diminishing response to deferoxamine with increasing time intervals, which suggests a gradual transit from a more available to a less available storage iron compartment. Mössbauer spectroscopy showed that practically all iron mobilized by deferoxamine was derived from the small (less than 3.0 nm) recently acquired iron particles, which supports the "last-in, first-out" principle. Quantitation of cytosolic ferritin iron particles has shown a highly reproducible increase in cytosolic ferritin iron after deferoxamine treatment. This intracellular redistribution of iron stores is explained either by a reduced transfer of cytosolic ferritin into siderosomes or, more likely, by increased mobilization of membrane-bound iron deposits from insoluble polynuclear iron complexes in siderosomes and their subsequent incorporation into cytosolic ferritin. Thus the protective effect of deferoxamine on iron-loaded heart cells may be twofold: (1) net removal of excess iron by the formation of a stable complex of iron with deferoxamine and its secretion into the extracellular environment and (2) a shift of solubilized iron from membrane-bound deposits into the cytosol where iron is detoxified by its incorporation into the hollow shell of the ferritin protein.

Animals↗
PubMed1991

Mutational analysis of the mitochondrial Rieske iron-sulfur protein of Saccharomyces cerevisiae. III. Import, protease processing, and assembly into the cytochrome bc1 complex of iron-sulfur protein lacking the iron-sulfur cluster.

We have used site-directed mutagenesis of the Saccharomyces cerevisiae Rieske iron-sulfur protein gene (RIP 1) to convert cysteines 159, 164, 178, and 180 to serines, and to convert histidines 161 and 181 to arginines. These 4 cysteines and 2 histidines are conserved in all Rieske proteins sequenced to date, and 4 of these 6 residues are thought to ligate the iron-sulfur cluster to the apoprotein. We have also converted histidine 184 to arginine. This histidine is conserved only in respiring organisms. The site-directed mutations of the six fully conserved putative iron-sulfur cluster ligands result in an inactive iron-sulfur protein, lacking iron-sulfur cluster, and failure of the yeast to grow on nonfermentable carbon sources. In contrast, when histidine 184 is replaced by arginine, the iron-sulfur cluster is assembled properly and the yeast grow on nonfermentable carbon sources. The site-directed mutations of the 6 fully conserved residues do not prevent post-translational import of iron-sulfur protein precursor into mitochondria, nor do the mutations prevent processing of iron-sulfur protein precursor to mature size protein by mitochondrial proteases. Optical spectra of mitochondria from the six mutants indicate that cytochrome b is normal, in contrast to the deranged spectrum of cytochrome b which results when the iron-sulfur protein gene is deleted. In addition, mature size iron-sulfur apoprotein is associated with cytochrome bc1 complex purified from a site-directed mutant in which iron-sulfur cluster is not inserted. These results indicate that mature size iron-sulfur apoprotein, lacking iron-sulfur cluster, is inserted into the cytochrome bc1 complex, where it interacts with and preserves the optical properties of cytochrome b. Insertion of the iron-sulfur cluster is not an obligatory prerequisite to processing of the protein to its final size. Either the processing protease cannot distinguish between iron-sulfur protein with or without the iron-sulfur cluster, or insertion of the iron-sulfur cluster occurs after the protein is processed to its mature size, possibly after it is assembled in the cytochrome bc1 complex.

Amino Acid Sequence↗
PubMed2005

Systemic iron supplementation replenishes iron stores without enhancing colon carcinogenesis in murine models of ulcerative colitis: comparison with iron-enriched diet.

Ulcerative colitis (UC) patients frequently require iron supplementation to remedy anemia. The impact of systemic iron supplementation (intraperitoneal injection) on UC-associated carcinogenesis was assessed in mice subjected to cyclic dextran sulfate sodium (DSS) treatment and compared with dietary iron enrichment. Systemic iron supplementation, but not a twofold iron diet, remedied iron deficiency as indicated by the histochemical detection of splenic iron stores. A twofold iron diet, but not systemic iron, increased iron accumulation in colonic luminal contents, at the colonic mucosal surface, and in superficial epithelial cells. Colitis-associated colorectal tumor incidence after 15 DSS cycles was not affected by systemic iron (2/28; 7.1%) compared to nonsupplemented controls (4/28; 14.1%) but was significantly increased by the twofold iron diet (24/33; 72.7%) (P < 0.001). Mechanistic study revealed that systemic iron had no effect on DSS-induced inflammation, or colonic iNOS and COX-2 protein levels, compared to controls. Systemic iron supplementation for 16 weeks replenished splenic iron in a spontaneous colitis model (interleukin-2-deficient mice) and significantly reduced colonic inflammation compared to interleukin-2 (-/-) controls without increasing hyperplastic lesions. These results suggest that iron supplemented systemically could be used to remedy anemia in UC patients without exacerbating inflammation or enhancing colon cancer risk. These findings need to be verified in clinical studies.

Adenocarcinoma↗
PubMed1998

Iron uptake in blood-brain barrier endothelial cells cultured in iron-depleted and iron-enriched media.

Iron is essential in the cellular metabolism of all mammalian tissues, including the brain. Intracerebral iron concentrations vary with age and in several (neurological) diseases. Although it is evident that endothelial cells lining the capillaries in the brain are of importance, factors governing the regulation of intracerebral iron concentration are unknown. To investigate the role of blood-brain barrier endothelial cells in cerebral iron regulation, primary cultures of porcine blood-brain barrier endothelial cells were grown in either iron-enriched or iron-depleted medium. Iron-enriched cells showed a reduction in surface-bound and total transferrin receptor numbers compared with iron-depleted cells. Transferrin receptor kinetics showed that the transferrin receptor internalization rate in iron-enriched cultures was higher, whereas the transferrin receptor externalization rate in iron-enriched cultures was lower than the rate in iron-depleted cultures. Moreover, blood-brain barrier endothelial cells cultured in iron-enriched medium were able to accumulate more iron intracellularly, which underlines our kinetic data on transferrin receptors. Our results agree with histopathological studies on brain tissue of patients with hemochromatosis, suggesting that at high peripheral iron concentrations, the rate of iron transport across the blood-brain barrier endothelial cells is to some extent proportional to the peripheral iron concentration.

Animals↗
PubMed1980

Comparative effects of iron deficiency induced by bleeding and a low-iron diet on the intestinal absorptive interactions of iron, cobalt, manganese, zinc, lead and cadmium.

Dietary iron deficiency enhances the absorption of iron, cobalt, manganese, zinc, cadmium and lead, whereas, iron deficiency due to bleeding increases the absorption of iron, cobalt and perhaps manganese. To determine whether the response to bleeding is qualitatively different from that induced by dietary iron deficiency, metal absorption was studied in mice fed either a high-iron diet (120 ppm Fe) and bled (0.5 ml) or fed a low-iron diet (< 3 ppm Fe). Iron absorption from an intragastric dose was increased by the loss of 0.5 ml of blood; smaller losses of blood had no effect. Also, iron absorption was increased more by dietary iron deficiency than by bleeding. In perfusion experiments, bleeding increased the duodenal absorption of only iron and cobalt, whereas dietary iron deficiency enhanced the absorption of all the metals except cadmium. The patterns of absorptive inhibition of the metals by each other were similar in bled mice and in mice with dietary iron deficiency except that interactions among metals with lower affinities for the iron absorption mechanism--manganese, zinc, cadmium and lead--were more obvious in mice fed the low-iron diet. We concluded that bleeding only partially activates the iron absorptive mechanism and that the lack of a bleeding effect on the absorption of manganese, zinc, cadmium and lead results from the weaker interactions of these metals, with a partly-activated absorption process.

Animals↗
PubMed1998

Adaptive response of iron absorption to anemia, increased erythropoiesis, iron deficiency, and iron loading in beta2-microglobulin knockout mice.

Recently, a novel gene of the major histocompatibility complex (MHC) class I family, HFE (HLA-H), has been found to be mutated in a large proportion of hereditary hemochromatosis (HH) patients. Further support for a causative role of HFE in this disease comes from the observation that beta2-microglobulin knockout (beta2m-/-) mice, that fail to express MHC class I products, develop iron overload. We have now used this animal model of HH to examine the capacity to adapt iron absorption in response to altered iron metabolism in the absence of beta2m-dependent molecule(s). Mucosal uptake, mucosal transfer and retention of iron were measured in control and beta2m-/- mice with altered iron metabolism. Mucosal uptake of Fe(III), but not of Fe(II), by the mutant mice was significantly higher when compared with B6 control mice. Mucosal transfer in the beta2m-/- mice was higher, independent of the iron form tested. No significant differences were found in iron absorption between control and beta2m-/- mice when anemia was induced either by repetitive bleeding or by hemolysis through phenylhydrazine treatment. However, iron absorption in mice made anemic by dietary deprivation of iron was significantly higher in the mutant mice. Furthermore, the beta2m-/- mice manifested an impaired capacity to downmodulate iron absorption when dietary or parenterally iron-loaded. The expression of the defect in iron absorption in the beta2m-/- mice is quantitative, with iron absorption being excessively high for the size of body iron stores. The higher iron absorption capacity in the beta2m-/- mice may involve the initial step of ferric mucosal uptake and the subsequent step of mucosal transfer of iron to the plasma.

Adaptation, Physiological↗