Role Of Iron Chelation Research Articles

Iron chelators as therapeutic agents against Pneumocystis carinii.

Iron plays a critical role in host-parasite interactions, and iron chelators have been demonstrated to serve as effective adjunct therapeutic agents against malaria. The effects of the parenteral iron chelator deferoxamine (DFO) on the growth of rat-derived Pneumocystis carinii were studied in a human fibroblast cell culture model and in two in vivo models of experimental infection. In addition, the effects of the investigational oral iron chelator CP20 and its 3-hydroxypyridin-4-one analogs CP51, CP94, and CP96 on the growth of P. carinii in vitro were assessed. DFO suppressed the growth of P. carinii in vitro in a dose-dependent manner, and daily injections of DFO markedly reduced the intensity of P. carinii infection in both mice and rats. Cell cultures treated with iron chelators that are administered orally to humans also showed substantial P. carinii growth inhibition. Reduction of P. carinii numbers after iron chelator therapy correlated with alterations in P. carinii morphology, as viewed by transmission electron microscopy. Since the use of current anti-P. carinii drugs is limited by toxicity or incomplete efficacy, or both, the role of iron chelation as adjunctive anti-P. carinii chemotherapy merits additional investigation.

Antiradical effects in l-propionyl carnitine protection of the heart against ischemia-reperfusion injury: The possible role of iron chelation

l-Propionyl carnitine has been shown to improve the heart's mechanical recovery and other metabolic parameters after ischemia-reperfusion. However, the mechanism of protection is unknown. The two dominating hypotheses are: (i) l-propionyl carnitine can serve as an energy source for heart muscle cells by being enzymatically converted to propionyl-CoA and subsequently utilized in the Krebs cycle (a metabolic hypothesis), and (ii) it can act as an antiradical agent, protecting myocardial cells from oxidative damage (a free radical hypothesis). To test the two possible pathways, we compared the protection afforded to the ischemia-reperfused hearts by l-propionyl carnitine and its optical isomer, d-propionyl carnitine. The latter cannot be enzymatically utilized as an energy source. The Langendorff perfusion technique was used and the hearts were subjected to 40 min of ischemia and 20 min of reperfusion. In analysis of ischemiareperfused hearts, a strong correlation was found between the recovery of mechanical function and the presence of protein oxidation products (protein carbonyls). Both propionyl carnitines efficiently prevented protein oxidation but l-propionyl carnitine-perfused hearts had two times greater left ventricular developed pressure. The results indicate that both metabolic and antiradical pathway are involved in the protective mechanism of l-propionyl carnitine. To obtain a better insight of the antiradical mechanism of l-propionyl carnitine, we compared the ability of l- and d-propionyl carnitines, l-carnitine, and deferoxamine to interact with: (i) peroxyl radicals, (ii) oxygen radicals, and (iii) iron. We found that none of the carnitine derivatives were able to scavenge peroxyl radicals or superoxide radicals. l- and d-propionyl carnitine and deferoxamine (not l-carnitine) suppressed hydroxyl radical production in the Fenton system, probably by chelating the iron required for the generation of hydroxyl radicals. We suggest that l-propionyl carnitine protects the heart by a dual mechanism: it is an efficient fuel source and an antiradical agent.

The role of iron chelates in the NAD(P)H-dependent oxidation of 2-keto-4-thiomethylbutyric acid (KMBA) by rainbow trout and pacific salmon microsomal fractions

Uninduced microsomes from three different species of the genus Oncorhynchus catalyzed a NAD(P)H-dependent oxidation of the radical scavenging agent 2-keto-4-thiomethylbutyric acid (KMBA). This reaction was stimulated by the addition of iron-EDTA, hemoglobin and myoblobin but inhibited by catalase and benzoate. Superoxide dismutase (SOD) did not substantially inhibit the oxidation in the presence of iron-EDTA. This hydroxyl radical (·OH)-generating system was mainly NADH-dependent which is similar to observations in aquatic invertebrates but in contrast to mammalian systems. This study demonstrates that this radical-generating activity is wide ranging and requires consideration in evaluating xenobiotic metabolism.

The role of iron chelates on the selectivity of Fenton reagent in hydroxylation, N-demethylation, and sulfoxidation of cimetidine: A novel biomimetic model for the regioselectivity of cytochrome P-450

The effect of iron chelates on the reaction of cimetidine with Fenton reagent [ Fe(II) H 2O 2 ]has been investigated. Iron chelates with high affinity to ferrous ions inhibited this reaction. However, iron chelates with high affinity to ferric ions selectively promote either hydroxylation, N-demethylation, or sulfoxidation of cimetidine. These results indicate that the oxidation of cimetidine with hydrogen peroxide activated by various chelated ferrous ions serves as a biomimetic model for the regioselectivity of multiple forms of cytochrome P-450 in the metabolism of cimetidine.

Role of iron chelators in growth-promoting effect on mouse hybridoma cells in a chemically defined medium.

The role of various iron chelators on the multiplication of mouse hybridoma cells in an albumin-free, transferrin-deficient defined medium was investigated. Fe(III)-dihydroxyethylglycine, Fe(III)-glycylglycine, Fe(III)-ethylenediamine-N,N'-dipropionic acid, or Fe(III)-iminodiacetic acid supported the excellent growth of the cells. In addition, the growth of the iron-starved cells, which had been preincubated in a protein-, iron- and chelator-free defined medium, restored rapidly when the medium was supplemented with holotransferrin, ferric iron, and chelator compared to that when supplemented with holotransferrin, but without iron and chelator. The results suggest that such chelators modulate a progression of transferrin cycle in the presence of transferrin and ferric iron. An alternative explanation is that there is a decrease in generation of iron-catalyzed free radicals.

Ethanol oxidation by hydroxyl radicals: role of iron chelates, superoxide, and hydrogen peroxide.

Oxygen-derived free radicals such as the hydroxyl radical (.OH) have been shown to mediate the oxidation of ethanol by a variety of oxy radical-generating systems. Among these are microsomal electron transport systems (both intact and purified, reconstituted systems), the coupled oxidation of hypoxanthine or xanthine by xanthine oxidase, and the model iron-ascorbate system. The sequence of reactions leading to the oxy radical-dependent oxidation of ethanol as well as other hydroxyl radical-scavenging agents by these various systems is believed to proceed through the formation of a common intermediate, namely, hydrogen peroxide (H2O2), after dismutation of the superoxide anion radical (O2-.). The presence of iron, especially chelated iron, greatly enhances the production of .OH by serving as an oxidant for O2-. or a reductant for H2O2. Experiments were carried out to evaluate the role of iron, the chelating agent, O2-., and H2O2 in the oxidation of ethanol by a variety of in vitro systems (chemical, enzymatic, and intact membrane bound) that can produce oxy radicals via different mechanisms. The generation of .OH by all the systems studied was sensitive to catalase, which indicates that H2O2 is the precursor of .OH. Superoxide radical appears to be the reducing agent in the hypoxanthine-xanthine oxidase system, indicating an iron-catalyzed Haber-Weiss reaction. In the ascorbate, reductase, and microsomal systems, superoxide radical does not appear to be the reducing agent. However, superoxide radical probably is the precursor of H2O2. While iron plays an important role in the production of .OH by the various systems, the effect of iron depends on the nature of the iron chelate.(ABSTRACT TRUNCATED AT 250 WORDS)

The role of iron chelates in hydroxyl radical production by rat liver microsomes, NADPH-cytochrome P-450 reductase and xanthine oxidase

Uninduced rat liver microsomes and NADPH-Cytochrome P-450 reductase, purified from phenobarbital-treated rats, catalyzed an NADPH-dependent oxidation of hydroxyl radical scavenging agents. This oxidation was not stimulated by the addition of ferric ammonium sulfate, ferric citrate, or ferric-adenine nucleotide (AMP, ADP, ATP) chelates. Striking stimulation was observed when ferric-EDTA or ferric-diethylenetriamine pentaacetic acid (DTPA) was added. The iron-EDTA and iron-DTPA chelates, but not unchelated iron, iron-citrate or iron-nucleotide chelates, stimulated the oxidation of NADPH by the reductase in the absence as well as in the presence of phenobarbital-inducible cytochrome P-450. Thus, the iron chelates which promoted NADPH oxidation by the reductase were the only chelates which stimulated oxidation of hydroxyl radical scavengers by reductase and microsomes. The oxidation of aminopyrine, a typical drug substrate, was slightly stimulated by the addition of iron-EDTA or iron-DTPA to the microsomes. Catalase inhibited potently the oxidation of scavengers under all conditions, suggesting that H 2O 2 was the precursor of the hydroxyl radical in these systems. Very high amounts of superoxide dismutase had little effect on the iron-EDTA-stimulated rate of scavenger oxidation, whereas the iron-DTPA-stimulated rate was inhibited by 30 or 50% in microsomes or reductase, respectively. This suggests that the iron-EDTA and iron-DTPA chelates can be reduced directly by the reductase to the ferrous chelates, which subsequently interact with H 2O 2 in a Fenton-type reaction. Results with the reductase and microsomal systems should be contrasted with results found when the oxidation of hypoxanthine by xanthine oxidase was utilized to catalyze the production of hydroxyl radicals. In the xanthine oxidase system, ferric-ATP and -DTPA stimulated oxidation of scavengers by six- to eightfold, while ferric-EDTA stimulated 25-fold. Ferric-desferrioxamine consistently was inhibitory. Superoxide dismutase produced 79 to 86% inhibition in the absence or presence of iron, indicating an iron-catalyzed Haber-Weiss-type of reaction was responsible for oxidation of scavengers by the xanthine oxidase system. These results indicate that the ability of iron to promote hydroxyl radical production and the role that superoxide plays as a reductant of iron depends on the nature of the system as well as the chelating agent employed.

Fe 3+-chelates mediate the oxidative modulation of cyanobacterial and chloroplast enzymes

Fe 3+-EDTA and the Fe 3+ complexes of naturally occurring compounds (ATP, ADP, GTP, oxalate, pyridoxal 5'-phosphate, P i, PP i) mediated the oxidative modulation of several, partially purified cyanobacterial and chloroplast enzymes. Cyanobacterial glucose-6-phosphate dehydrogenase deactivated by treatment with dithiothreitol + thioredoxin was reactivated in the presence of Fe 3+-chelates under aerobic conditions. Cyanobacterial fructose-1,6-bisphosphatase, spinach leaf NADP-glyceraldehyde-3-phosphate dehydrogenase and NADP-malate dehydrogenase activated by incubation with dithiothreitol + thioredoxin were deactivated in the presence of Fe 3+-chelates under aerobic conditions. Cyanobacterial isocitrate dehydrogenase and cyanophage AS-1-induced site-specific endonuclease, enzymes known to be devoid of redox properties, were not affected by the Fe 3+ complexes. The possible role of iron-chelates in enzyme modulation is discussed.

A model chapter on iron for a textbook on plant nutrition

Abstract New ideas are being developed on iron relationships in plants. Older textbooks on plant nutrition are obsolete in respect to iron and some newer textbooks are somewhat obsolete. It is very important that students be kept near the front of this changing field to insure that progress continues. The chapter by Mengel and Kirkby (1982) is excellent although it does not go into siderophores and their possible relationships with iron uptake and to microbial and crop ecology, or deeply into redox in relationship with uptake of iron from synthetic chelating agents, or into iron uptake by plants from organic iron amendments, or into the riboflavin aspect of the iron response mechanism, or into hormonal control of iron transport, or into the role of iron chelates on the flowering of Lemna, or into the role of iron on thylakoid synthesis or much into the diagnosis of iron status of plants and soils as examples, or much into the significance of iron interactions in ecological problems related to lime soils. The chapter does a good work of putting together the iron stress response mechanism and its characteristics although it could expand more into its genetic control.