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At least 19 recordsLinked to original sources
PubMed1978

Biological activities of pyochelins: iron-chelating agents of Pseudomonas aeruginosa.

Strains of Pseudomonas aeruginosa able to grow readily in serum (serum resistant) produce siderophores in large quantity, enabling them to extract iron from transferrins. The term pyochelin has been proposed for this group of compounds. Pyochelin extractable with ethyl acetate and designated pyochelin A appears to be a mixture of catechols and other phenolates. The structures of water-soluble siderophores, designated pyochelin B, have not been determined. Pyochelins enabled growth in serum of strains of serum-sensitive P. aeruginosa and other gram-negative bacilli. Serum-resistant strains of P. aeruginosa tended to be more virulent than equally toxigenic strains of the serum-sensitive group. However, incorporation of pyochelins into the inocula of serum-sensitive strains could reduce, rather than enhance, their virulence. Utilization of pyochelins by serum-sensitive strains of P. aeruginosa rendered some of these organisms resistant to pyocins which were otherwise lethal to them.

Bacteria↗
PubMed1976

The effect of chelating agents on iron mobilization in Chang cell cultures.

The investigation of chelating agents with potential therapeutic value in patients with transfusional iron overload has been facilitated by the use of Chang cell cultures. These cells have been incubated with [59Fe]transferrin for 22 hr, following which most of the intracellular radioiron is found in the cytosol, distributed between a ferritin and a nonferritin form. Iron release from the cells depends on transferrin saturation in the medium, but when transferrin is 100% saturated, which normally does not allow iron release, desferrioxamine, 2,3-dihydroxybenzoic acid, rhodotorulic acid, cholythydroxamic acid, and tropolone all promote the mobilization of ferritin iron and its release from cells. They are effective to an approximately equal degree. The incubation of [59Fe]transferrin with tropolone in vitro at a molar ratio of 1:500 results in the transfer of most of the labeled iron to the chelator, reflecting the exceptionally high binding constant of this compound. How far these phenomena relate to therapeutic potentially remains to be seen.

Anemia, Hypochromic↗
PubMed1978

Iron transport by isolated rat intestinal mucosal cells.

In vitro uptake of radioiron by suspensions of isolated rat duodenal mucosal cells has been examined. The cells bind iron avidly, with uptakes of 15 to 20% after 20 min of incubation. Uptake is dependent upon temperature, pH, and iron and cell concentration. It is unaffected by inhibitors of cellular respiration but is blocked in a concentration-dependent fashion by iron-chelating agents. Iron-deficient cells take up iron at the same rate as normal cells. Binding by brush borders appears to account for 50 to 60% of the total uptake by isolated cells. In vitro radioiron uptake by isolated cells occurs by passive diffusion, is not regulated by the animal's iron status, and is primarily a function of bioavailability of iron in the incubating medium. If the model reflects the behavior of cells in vivo, the initial uptake of iron by the mucosa is a passive process which may serve to concentrate dilute luminal iron at the mucosal surface in preparation for absorption.

Animals↗
PubMed1976

The use of chang cells cultured in vitro to evaluate potential iron chelating drugs.

A number of iron chelating agents, consisting largely of hydroxamic acid and benzoic acid derivatives, have been studied in an in vitro Chang cell culture system to determine their effect on cellular iron uptake, ferritin synthesis and the incorporation of iron into ferritin. The results have been compared with those of a previous study in which iron balance was determined in hypertransfused rats. Both techniques appear to be of value in screening new iron chelating agents for potential therapeutic use in patients with iron overload.

Benzoates↗
PubMed1976

The effect of chelating agents on cellular iron metabolism.

1. The effect of iron chelators on iron uptake, ferritin and total protein synthesis was studied in cultured Chang cells. Desferrioxamine depressed ferritin synthesis and completely inhibited iron uptake by ferritin protein. Rhodotorulic acid reduced iron uptake by the cells but had little effect on ferritin synthesis. Diethylenetriamine pentaacetic acid produced complete inhibition of iron uptake and all protein synthesis. 2,3-Dihydroxybenzoic acid (2,3-DHB) had no effect in this system. 2. When 2,3-DHB was incubated with a liver homogenate, its subsequent addition to a Chang cell culture resulted in depression of ferritin synthesis, iron uptake into the protein and some depression of total protein synthesis. Pretreatment of rhodotorulic acid did not affect its properties. 3. Non-ferritin iron in the Chang cell cytosol was dialysable, available for binding to transferrin and formed chelates which appeared, on gel chromatography, to be of low molecular weight. Gel chromatography of cytosol after incubation of the cells with chelating agents showed non-ferritin iron to be in a similar form. 4. Loss of non-ferritin iron from the cells occurred only when the transferrin in the medium was unsaturated. In the presence of chelating agents non-ferritin iron was lost from the cells even when transferrin was 100% saturated. 5. The results confirm the presence of an intracellular labile iron pool which is available for chelation, and demonstration that different iron chelators have different metabolic effects.

Binding Sites↗
PubMed1979

Inhibition of the growth of Neisseria meningitidis by reduced ferritin and other iron-binding agents.

Serogroups of N. meningitidis were characterized as virulent or avirulent according to their capacity to establish meningococcal infection in mice. An agar plate diffusion technique demonstrated that iron had a definite growth-supporting role for both of these meningococcal types. The avirulent strains could use ionic or chelated iron as well as the virulent strains. Iron-reversible growth inhibition occurred to the same extent for both bacterial types in the presence of the synthetic iron-chelating agents Desferal and ethylenediamine-di-orthohydroxy phenylacetic acid. A difference in response was demonstrated for these bacterial types when grown in the presence of various iron-binding proteins from animal body fluids and tissues. The growth of the avirulent strain was inhibited to a greater degree by egg white conalbumin. The humoral iron-binding protein transferrin showed a significant inhibitory capacity only when used in conjunction with bicarbonate. Under conditions of increased iron saturation of this protein, the avirulent strain was inhibited to the furthest extent. In the presence of ferritin, the cellular iron-binding protein, which had been reduced, inhibition of the growth of either strain type did not occur on iron-poor media (less than 5 micrograms/100 ml). However, with the incorporation of iron into the media, the inhibitory effect of the protein became evident. As the concentration of iron increased, the inhibition increased to a certain level and subsequently declined. A substantial difference in the ability of the avirulent type to grow in the presence of reduced horse spleen ferritin was observed. For this microorganism, a correlation appears to exist between the capacity to grow by utilizing the available iron in the presence of reduced ferritin and the ability to establish infection. The host protein ferritin, in the reduced state, apart from simply being a storage protein for iron, can prevent the growth of a procaryotic organism. Our experiments suggest a role for ferritin in the prevention of emningococcal disease. A cehmotherapeutic potential for Desferal is also implied.

Conalbumin↗
PubMed1976

Formation of monoferric ovotransferrins in the presence of chelates.

1. When ovotransferrin is partially saturated with iron, endotherms for apo-ovotransferrin, two monoferric ovotransferrins and Fe2-ovotransferrin are observed by differential scanning calorimetry. The relative sizes of the endotherms are changed in the presence of the iron-chelating agents nitrilotriacetic acid and ATP. 2. When iron is added as Fe(III)-nitrilotriacetate, at Fe-nitrilotriacetate: ovotransferrin ratios less than unity, the endotherm for Fe2-ovotransferrin is essentially absent. At Fe-nitrilotriacetate: ovotransferrin ratios of unity the only species present in solution in appreciable concentration as evidenced by their differential-scanning-calorimetry endotherms, are two monoferric ovotransferrins in approximately equal amounts. At Fe-nitrilotriacetate: ovotransferrin ratios greater than unity, the apo-ovotransferrin endotherm is absent, and the endotherms for the two monoferric ovotransferrins decrease in size as the endotherm for Fe2-ovotransferrin increases. 3. In the presence of nitrilotriacetate, binding of iron to the two sites of ovotransferrin is highly anti-co-operative, but essentially indiscriminate. When monoferric ovotransferrin is formed from apo-ovotransferrin, binding at one site is slightly favoured compared with binding at the other site, but once iron has been bound at either site, the binding affinity for iron at the unoccupied site is much decreased.

Adenosine Triphosphate↗
PubMed1976

Thalassemia in Italy: treatment of Cooley disease and iron kinetics in heterozygotes.

Because of its high prevalence in Italy, thalassemia is officially considered a disease of major social importance. Several centers have been established for the specific purpose of population screening and treatment of patients with Cooley disease. Survival, in some cases up to 20 years, has been reached by the therapeutic methods adopted, consisting mainly of an intensive transfusion program combined with splenectomy. We now face serious logistic, social, and financial problems, raised by the increasing number of patients living, estimated at around 12,000. The iron overload is not adequately controlled by the routine use of desferrioxamine. Studies of iron kinetics in heterozygotes demonstrate specific alteration of iron metabolism (not related to the exogenous transfusion-induced overload). Therefore, treatment with iron-chelating agents might be indicated in at least some of these subjects.

Adolescent↗
PubMed1978

Iron chelation therapy with deferoxamine in Cooley anemia.

The iron-chelating agent, deferoxamine, was studied in 16 patients with thalassemia major. Urinary excretion of iron in response to 0.75 gm of deferoxamine, intramuscularly, ranged from 2.2 to 44.8 mg Fe/24 hours. In response to a subcutaneous infusion of 1.5 gm deferoxamine for 18 hours, iron excretion increased by an average of 240%. The intravenous infusion of large doses of deferoxamine for 18 hours resulted in the highest rate of iron excretion, as much as 447.5 mg Fe/24 hours in response to 16 gm of deferoxamine. Administration of vitamin C increased chelation-induced excretion of iron in most patients more than five years of age. Preliminary evidence suggests that further iron accumulation can be prevented and excessive iron stores can be depleted by the intramuscular, subcutaneous, or intravenous administration of deferoxamine.

Adolescent↗
PubMedDate not supplied

Lens opacities in thalassemia.

This is the first case report of cataracts in patients with thalassemia major. Desferrioxamine, an iron-chelating agent is being used with increasing frequency in the treatment of transfusion-induced iron overload. There has been some concern in the literature about possible cataract formation with use of this drug. It is therefore important to document any lens opacities seen prior to administration of desferrioxamine, or record the appearance of lens opacities after its use. The possible eitology of these lens opacities is discussed.

Adolescent↗
PubMed1976

A rabbit reticulocyte model for the role of hemin-controlled repressor in hypochromic anemias.

Hemin allows maximal protein synthesis in intact rabbit reticulocytes and their cell-free lysate preparations by retarding the formation of a translational repressor (HCR) found in the postribosomal supernate. In order to evaluate the role of HCR in the pathogenesis of hypochromic anemias, HCR was isolated and partially purified from intact rabbit reticulocytes incubated in vitro with either 0.1 mM alpha,alpha-dipyridyl (an iron-chelating agent) or 0.1 M ethanol. Both of these agents inhibit reticulocyte protein synthesis. Hemin (50 muM) protects against the inhibition by both agents. A ferrous iron-transferrin mixture, however, protects only against alpha,alpha-dipyridyl. Both alpha,alpha-dipyridyl and ethanol inhibit heme synthesis before the time that protein synthesis is affected, while neither lowers either ATP or GSH levels. These results indicate that while both agents inhibit heme synthesis, alpha,alpha-dipyridyl does so by inducing iron deficiency while ethanol works at a non-iron-requiring step. When HCR was isolated from intact cells and assayed in the reticulocyte cell-free systems, plus and minus hemin, premature appearance of HCR was found in cells incubated in vitro with alpha,alpha-dipyridyl or ethanol. When hemin was present in the intact cell incubation, the appearance of HCR was retarded. The HCR from alpha,alpha-dipyridyl ethanol-treated cells was partially purified and eluted at the same location on a Sephadex G-200 column (molecular weight approximately 3 x 10(5)) as that from postribosomal supernates incubated minus hemin. In addition rabbits with phenylhydrazine-induced hemolytic anemia were given intravenous ethanol in vivo at a dose of 0.4 ml/kg. This concentration of alcohol resulted in an inhibition of the rate of heme synthesis and protein synthesis as well as an acceleration of HCR formation in reticulocytes. The HCR from these in vivo treated rabbits was isolated, partially purified, and assayed in an identical fashion as the in vitro experiments. These in vivo experiments further support the physiological and pathophysiological role of HCR in reticulocytes. On the basis of these results a model for a role of HCR in some of the hypochromic anemias is proposed. In iron deficiency or chronic disease (where iron is not available to the erythroblast for heme synthesis) HCR appears prematurely and inhibits protein synthesis. When heme synthesis is inhibited by ethanol but there is sufficient intracellular iron, HCR appears prematurely and inhibits protein synthesis, iron accumulates in the erythroblast, and the end result is sideroblastic anemia.

2,2'-Dipyridyl↗
PubMed1978

A noninvasive method for the evaluation of tissue iron deposition in beta-thalassemia major.

DXS, a noninvasive method for the analysis and quantitation of trace elements in different tissues, was applied to quantitate the degree of iron overload in the skin of 19 patients with beta-thalassemia major. The duration of the test is short, it is not associated with inconvenience to the patient, and it can be repeated at different times at different locations on the outer surface of the body. In patients who receive numerous repeated blood transfusions, there was a close correlation between the dermal iron content and the rate of transfusions when they exeeded 6 units of packed RBC per year. In three patients with the spleen in situ, the dermal iron content was lower than in corresponding splenectomized patients. The rate of dermal iron accumulation was found to be similar to the rate of iron deposition in the liver, as assessed in a similar group of patients by repeated liver biopsies. The monitoring of the degree of iron accumulation in individual patients as a function of time and the effect of treatment with iron chelating agents can be determined noninvasively with the aid of DXS.

Blood Transfusion↗
PubMed1976

The development of new iron-chelating drugs.

2,3-Dihydroxybenzoic acid has been identified as a potentially useful iron-chelating drug. Accordingly, we have evaluated a series of derivatives of hydroxylated benzoic acids for their ability to induce iron excretion in the iron-overloaded rat. In addition, we have examined a number of hydroxamic acids and some other naturally occurring iron-chelating agents. Of the 26 benzoic acid derivatives studied, none appeared to be more effective than 2,3-dihydroxybenzoic acid, for reasons which are discussed. Rhodotorulic acid, a hydroxamic acid produced by and isolated from cultures of Rhodotorula pilimanae, was the most effective of all the compounds studied in inducing iron excretion. When administered parenterally, rholotorulic acid induced iron excretion via both the urinary and the fecal routes and was more than twice as potent (on a weight basis) as desferrioxamine. Two ferrous chelators, alpha, alpha-dipyridyl ad 1,10-phenanthroline, induced a moderate amount of iron excretion, suggesting that a pool of ferrous iron may be available for chelation.

Animals↗
PubMed1978

The role of iron in prostaglandin synthesis: ferrous iron mediated oxidation of arachidonic acid.

Arachidonic acid (AA) is the essential substrate for production of platelet endoperoxides and thromboxanes. Iron or heme is an essential cofactor for the peroxidase, lipoxygenase and cyclo-oxygenase enzymes involved in formation of these products. The present study has examined the direct interactions between iron and arachidonic acid. Iron caused the oxidation of AA into more polar products which could be detected by UV absorbtion at 232 nM or the thiobarbituric acid (TBA) reaction. High pressure liquid chromatography, chem-ionization and electron-impact mass spectrometry and nuclear magnetic resonance spectroscopy suggest that the major product was a hydroperoxide of AA. Ferrous iron (Fe++) and oxygen were absolute requirements. Fe++ was converted to the ferric iron (Fe+++) state during oxidation of AA, but Fe+++ could not substitute for Fe++. No other enzymes, cofactors or ions were involved. Conversion of AA to a hydroperoxide by Fe++ was inhibited by the antioxidant, 2, (3)-Tert-butyl-4-hydroxyanisole, the radical scavenger, nitroblue tetrazolium, and iron chelating agents, including EDTA, imidazole and dihydroxybenzoic acid. The reaction was not affected by superoxide dismutase, catalase or aspirin. These findings and preliminary studies of the Fe++ induced oxidation product of AA as a substrate for prostaglandin synthesis and inhibitor of prostacyclin production indicate the critical role of Fe++ in AA activation.

Antimetabolites↗