Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanisms of iron uptake from transferrin and the effects of iron chelators on these processes were investigated in human neuroblastoma cells. This study was performed because numerous reports have indicated that neuroblastoma cells contain iron-rich ferritin and are also especially sensitive to iron chelation by deferoxamine. The mechanisms of iron and transferrin uptake were examined in the human neuroblastoma cell line SK-N-MC by using human transferrin labeled with iodine 125 and iron 59. Internalized and membrane-bound 59Fe and 125I-transferrin were separated with the protease pronase. Total internalized and membrane 125I-transferrin uptake was biphasic with time, whereas total and internalized 59Fe uptake was linear. Iron uptake from transferrin was prevented by incubation at 4 degrees C and also by lysosomotrophic agents. In addition, 59Fe uptake occurred by two processes. The first process was consistent with receptor-mediated endocytosis involving internalization of transferrin bound to specific binding sites. Iron uptake also occurred by a second process, which was not saturable up to a transferrin concentration of 0.06 mg/ml. In terms of quantitative iron uptake, however, the second process was far less important than receptor-mediated endocytosis. Deferoxamine (0.25 mmol/L) only slightly increased 59Fe release from prelabeled cells; the orally effective iron chelator pyridoxal isonicotinoyl hydrazone (0.25 mmol/L) was six times more effective. Moreover, when pyridoxal isonicotinoyl hydrazone (0.2 mmol/L) was added together with labeled transferrin over a 2-hour incubation, 59Fe uptake from transferrin decreased to 18% of the control value, whereas deferoxamine (0.2 mmol/L) had no appreciable effect. Even though deferoxamine (0.1 mmol/L) had little effect on 59Fe uptake or release, it reduced uptake of tritiated thymidine to 33% of the control value after a 24-hour incubation. Three analogs of pyridoxal isonicotinoyl hydrazone, pyridoxal benzoyl hydrazone (#101), pyridoxal p-methoxybenzoyl hydrazone (#107), and pyridoxal m-fluorobenzoyl hydrazone (#109), had chelation activities comparable to that of pyridoxal isonicotinoyl hydrazone and were more effective than either deferoxamine or pyridoxal isonicotinoyl hydrazone at preventing tritiated thymidine uptake. These results suggest that the pyridoxal isonicotinoyl hydrazone analogs have potential as effective antiproliferative agents and deserve further investigation.
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PMID:The iron metabolism of the human neuroblastoma cell: lack of relationship between the efficacy of iron chelation and the inhibition of DNA synthesis. 796 24

Nine iron overloaded patients were treated with L1--Deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one) in daily dose 3 g (40-50 mg/kg) for 12 weeks. In 7 patients the efficiency of L 1 treatment was compared to the therapeutic effect of the same dose of desferrioxamine (Desferal). A significant increase in urinary iron excretion was observed after administration of both chelating agents. Iron excretion after L 1 treatment was approximately 65% of that obtained with Desferal. The amount of excreted iron correlated with the amount of iron stores before chelation. A significant decrease in transferrin saturation, serum and red cell ferritin was observed after treatment with Desferal, L 1 administration caused a significant decrease only in serum ferritin level. However, all the parameters reflecting iron stores remained increased when compared to normal values after 12 weeks of chelation therapy. An incomplete absorption from gut and some reutilization of chelated iron may be responsible for less potent iron chelation by L 1 in comparison to Desferal. A low tolerance of the drug together with repeated nausea and vomiting were the most frequent adverse effects observed in the course of L1 administration. L 1 treatment had to be discontinued due to repeated vomiting in one patient and due to progressive granulocytopenia and thrombocytopenia in another patient. Because of the side effects more clinical studies with L 1 are needed before its introduction in wide clinical practice.
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PMID:[Treatment of iron overload states with oral administration of the chelator agent, L1 (Deferiprone)]. 797 62

Patients on a moderate red cell transfusion programme have iron overload where the concentrations of the serum ferritin were inappropriate to increases in the transfusion load as a result of limitations of apoferritin synthesis and conversion of ferritin into haemosiderin. This study confirms the limitations for the use of estimations of the serum ferritin to evaluate the iron status in patients with expected high overload as would be seen in patients on many years of maintenance red cell transfusions in the absence of iron chelation therapy. Poor compliance, inadequate dosage of Desferal (deferoxamine), and the late initiation of iron chelation therapy were factors that were considered in the patients with failure of response to iron chelation.
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PMID:Serum ferritin concentrations in transfusion dependent beta-thalassaemia. 800 83

Lactic acid 4 mM acted as a lipoperoxidant by increasing production of thiobarbituric acid-reactive substances (TBARS) in rat kidney slices and homogenates. This effect occurred mainly when slices and homogenates were incubated in a pH 5.4 medium conductive to full expression of compound acidity. TBARS increase was only slight when incubation was performed in Krebs buffer, pH 7.4. Moreover, sodium lactate 4 mM increased TBARS production only when homogenates were incubated in the pH 5.4 medium. Deferoxamine (1 mM) inhibited the prooxidant effect of lactic acid 4 mM, and TBARS increase was correlated with iron release. The iron mobilized may come from reserves where it is weakly bound or from ferritin; and ascorbic acid, present in low quantities in kidney, might trigger the release of this product.
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PMID:Iron- and lactic acid-induced lipid peroxidation in rat kidney homogenates and slices. 811 16

Post-transfusional iron overload is a real problem for doctors in charge of transfusions, as shown by the survey we led in twenty French blood banks. Deferoxamine remains the most efficient chelator, but can be prescribed only in a parenteral way. It is now proved that continuous infusions, intravenous or subcutaneous, are preferable to intermittent injections as far as iron excretion is concerned. In our study, we selected 15 polytransfused patients for dysmyelopoiesis. 13 cases were analysed by measuring the serum ferritin level. A clear decrease was noted, as well as a relative normalization of serum alanine amino transferases. However, if this treatment is effective and well tolerated, the problem is that it obviously requires the patient's compliance. It seems important to us to optimize prevention and treatment of post-transfusional iron overload through a consensus.
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PMID:[Post-transfusion hemochromatosis. Results of a study carried out in Blood Transfusion Centers. Analysis of 15 cases treated with subcutaneous perfusion of Desferal. Working group "Transfusion Techniques and Therapeutics"]. 818 55

The mechanism of action of the clinically used iron(III) chelator, desferrioxamine (DFO), on preventing iron (Fe) uptake from transferrin (Tf) has been investigated using the human melanoma cell line SK-MEL-28. This investigation was initiated due to the paucity of information on the mechanisms of action of DFO in neoplastic cells and because recent studies have suggested that DFO may be a useful antitumor agent. The effect of DFO was dependent on incubation time. After a 2-h incubation, DFO acted like the extracellular chelators, EDTA and diethylenetriaminepentaacetic acid, because there was little inhibition of 59Fe uptake from Tf. In contrast, after a 24-h incubation, DFO (0.5 mM) efficiently reduced internalized 59Fe uptake from Tf to 18% of the control value. These observations suggested the existence of a kinetic block to the entry of the apochelator to intracellular Fe pools and/or to the exit of the DFO-59Fe complex. Indeed, cellular fractionation demonstrated that, in contrast to the decrease in the percentage of 59Fe in the ferritin and membrane fractions, a marked increase in the percentage of 59Fe present in the ferritin-free cytosol occurred. These observations suggested an accumulation of the DFO-59Fe complex within the cell. The highly lipophilic Fe chelator, pyridoxal isonicotinoyl hydrazone, was far more effective than DFO at preventing 59Fe uptake from Tf, illustrating the importance of membrane permeability for effective Fe chelation. Desferrioxamine at a concentration of 1 mM decreased internalized 125I-Tf uptake to 70% of the control. However, the decrease in 59Fe uptake observed could only be partially accounted for by a decrease in Tf uptake, and it appeared that DFO was chelating 59Fe at an intracellular site consistent with the transit Fe pool. The results are discussed in the context of the use of Fe chelators as effective antineoplastic agents.
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PMID:The effect of the iron(III) chelator, desferrioxamine, on iron and transferrin uptake by the human malignant melanoma cell. 830 30

The ability of cells to re-repress ferritin synthesis after removal of an inducing agent (iron or heme) was investigated. Re-repression was found to be a slow process, requiring approximately 4 (after iron removal) to 10 h (after heme removal) for completion. Desferrioxamine mesylate (Desferal) had only a slight effect on the rate of re-repression, whereas cycloheximide was strongly inhibitory, indicating that new protein synthesis is required for re-repression. Re-repression occurred at a slow but significant rate in the presence of both Desferal and cycloheximide. These results indicate that, in the absence of an iron chelator, the induction of ferritin synthesis is essentially irreversible. The kinetics of the previously reported covalent modification of IRE-binding protein (IRE-BP) were then examined, to see whether this phenomenon might account (at least in part) for the irreversibility of induction. It was found that the heme- or iron-dependent disappearance of 98-kDa IRE-BP occurred rapidly (within 1 h), and was equally rapidly reversed upon removal of heme after a 1-h exposure. By contrast, after a 4-h exposure to heme, little 98-kDa IRE-BP could be regenerated after heme removal. These results suggest that the slow, irreversible covalent modification of IRE-BP correlates closely over time with the induction of ferritin synthesis. The covalent modification of IRE-BP depends on cell growth rate, and is most readily detected in rapidly growing cells.
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PMID:Irreversible steps in the ferritin synthesis induction pathway. 830 3

When erythrocyte membranes were incubated with adriamycin (ADM) in the presence of ferritin, lipid peroxidation occurred with release of iron from the ferritin. In the presence of apoferritin, ADM did not cause lipid peroxidation. Deferoxamine inhibited the ADM-induced lipid peroxidation in the presence of ferritin. These results indicate that lipid peroxidation depends upon the release of iron from ferritin. Even when the iron content in ferritin was very low, ADM could induce lipid peroxidation. Superoxide dismutase, catalase and hydroxyl radical scavengers did not substantially affect lipid peroxidation, indicating that the peroxidation reaction was independent of superoxide, H2O2 and hydroxyl radicals. Ceruloplasmin, a ferroxidase, markedly inhibited lipid peroxidation but did not affect the release of iron from ferritin. ADM-Fe(3+)-binding erythrocyte membranes were readily formed during the incubation of erythrocyte membranes with ADM in the presence of ferritin, and deferoxamine removed iron from the ADM-Fe(3+)-binding membranes, indicating that the iron moiety of the ADM-Fe(3+) complex is exposed at the membrane surface. These results may suggest that the peroxidation reaction occurs in a site-specific manner.
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PMID:Adriamycin-induced lipid peroxidation of erythrocyte membranes in the presence of ferritin and the inhibitory effect of ceruloplasmin. 840 98

The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.
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PMID:The possible role of iron in the etiopathology of Parkinson's disease. 841 92

We have studied the response of hemoglobin (Hb), hematocrit, reticulocytes, mean corpuscular volume, ferritin, serum iron, total iron-binding capacity (TIBC) and the transferrin saturation index in 9 patients on chronic hemodialysis (HD) with minimal aluminum overload who were treated with recombinant human erythropoietin (rHuEPO) when a single dose of deferoxamine (DFO; 40 mg/kg b.w.) was administered. Analytical determinations were performed basally and 48 h, 7 days and 14 days after a DFO test. Hb increased from a basal value of 10 +/- 0.28 to 10.7 +/- 0.33 (p < 0.05), 10.4 +/- 0.33 (p < 0.05) and 10.1 +/- 0.31 g/dl (NS), respectively, and similar increases were seen with the hematocrit. Serum iron increased from 52 +/- 7.62 to 89.2 +/- 14.48 (p < 0.01), 94 +/- 18.73 (p < 0.01) and 85 +/- 14.01 micrograms/dl (p < 0.01), respectively. TIBC and ferritin did not change but the transferrin saturation index increased significantly. DFO produces an immediate improvement of the anemia in HD patients treated with rHuEPO and who have minimal aluminium accumulation: it should be related to an increased iron availability to erythroid precursors either releasing stored iron or decreasing aluminum-bound transferrin.
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PMID:Direct effect of deferoxamine on hemoglobin synthesis in patients on hemodialysis treated with recombinant human erythropoietin. 845 Sep 6


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