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RENAL PHYSIOLOGY
Year : 2007  |  Volume : 17  |  Issue : 4  |  Page : 188-193
 

Role of non-transferrin-bound iron in chronic renal failure and other disease conditions


Department of Biochemistry, Kasturba Medical College, Manipal, Karnataka, India

Correspondence Address:
M Prakash
Department of Biochemistry, Kasturba Medical College, Manipal - 576104
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0971-4065.39169

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  Abstract 

Iron is an essential transitional metal required by the body for various biological functions. Iron is securely stored in ferritin and other biomolecules, either in ferrous or ferric state, and there are safe mechanisms for its storage or release from proteins to catalyze biological reactions. Under stress or some pathological conditions, there occurs the release of free iron or non-transferrin bound iron, which is free from its protein bound form, and it undergoes Fenton and Heiber-Weiss reactions to generate powerful reactive oxygen species. The reactive oxygen species generated will damage the biological macromolecules. It has been proved that in uremia or chronic renal failure patients, on conservative management or on hemodialysis program or under many other disease conditions, free iron or non-transferrin bound iron does exist; it induces damage to the biomolecules, thereby enhancing the disease process. In this review I have discussed the role of free iron or non-transferrin iron in general in biology and medicine, particulary in chronic renal failure.


Keywords: Chronic renal failure, hemodialysis, iron


How to cite this article:
Prakash M. Role of non-transferrin-bound iron in chronic renal failure and other disease conditions. Indian J Nephrol 2007;17:188-93

How to cite this URL:
Prakash M. Role of non-transferrin-bound iron in chronic renal failure and other disease conditions. Indian J Nephrol [serial online] 2007 [cited 2020 Nov 30];17:188-93. Available from: https://www.indianjnephrol.org/text.asp?2007/17/4/188/39169



  Iron in Biological System Top


Since the evolution of earliest life forms, iron has been an important metal ion in many biochemical reactions catalyzed both enzymatically and non-enzymatically. The abundance of iron in the environment and its chemical properties dictate that multicellular organisms must have extremely efficient mechanisms for iron accumulation, delivery and storage. Transferrin, an iron binding protein, transports ferric (Fe +3 ) iron (a predominant form of iron) that is relatively insoluble at physiological pH and prevents iron from precipitating. Specific cell surface receptors for transferrin facilitate and regulate cellular iron uptake. Although iron is required for many biologically important enzymatic reactions, it must be sequestered safely to prevent toxicity. About two-thirds of body iron is found in hemoglobin and smaller amounts in myoglobin, various enzymes and transferrin. Storage iron is the second largest iron compartment in the body and most of it is found in hepatocytes and macrophages, where it is sequestered in ferritin [Table - 1]. Ferritin stores iron in a nonreactive form that can be mobilized readily whenever required by the body. [1]


  Transition Metals Promote Free Radical Production Top


In the presence of transition metal ions such as iron or copper and superoxide (O 2 - ∙), hydrogen peroxide (H2 O 2 ) can give rise to the highly reactive OH . (hydroxyl radical) species. [2],[3]

M +n + H 2 O 2 → M + (n + 1) + OH . + OH -

Here, M +n can be any transitional metal ion. In 1894, Fenton described the oxidizing potential of hydrogen peroxide mixed with ferrous salts. [4]

Fe +2 + H 2 O 2 → Fe +3 + OH . + OH -

Forty years later, in 1934, Haber and Weiss identified the hydroxyl radical as the oxidizing species in these reactions: [4]

O2- ∙ + H 2 O 2 → O 2 + OH - + OH .

Overall summation of Fenton reaction in two steps gives the Haber-Weiss reaction

Fe +2 + H 2 O 2 → Fe +3 + OH + OH -

Fe +3 + O 2 - ∙ → Fe +2 + O 2
------------------------------------------------------
O 2 - ∙ + H 2 O 2 → O 2 + OH - + OH

In fact, Fenton chemistry is far more complex than stated in the above equations. The intermediate oxo-iron complexes, possibly ferryl or perferryl compounds, may be involved; further, these complexes decompose to form OH . radicals. [3]

Fe +2 + H 2 O 2 → FeOH -3 (or FeO -2 ) → OH + Fe +3

Fe +3 + O 2 - ∙ ↔ (Fe +3 - O 2 ↔ Fe +2 - O 2 ) Fe +2 + O 2

Thus, the sum of these reactions, ignoring the oxo-iron intermediates, is

O 2 - ∙ + H 2 O 2 Fe →O 2 + OH - + OH

This reaction is often called the iron-catalyzed Haber-Weiss reaction, or sometimes the superoxide-driven Fenton reaction.

In biological systems, the availability of ferrous ion limits the rate of reaction; however, the recycling of iron from the ferric to the ferrous form by a reducing agent can maintain an ongoing Fenton reaction, thereby leading to the generation of hydroxyl radicals. [4],[5] One suitable reducing agent is superoxide; it participates in the reduction of ferric iron to ferrous form. Therefore, in the presence of trace amounts of iron, the reaction of superoxide and hydrogen peroxide will lead to the formation of the destructive hydroxyl radical, and it initiates the oxidation of organic substrates. [3],[4] Another important biological reducing agent is ascorbic acid; when both O 2- ∙ and ascorbate are available, the relative contributions of each of them to the OH∙ production depends on their concentrations. [6] Ascorbate in the concentrations normally present in human extracellular fluids can at most partially replace O 2- ∙ while reducing Fe +3 ; however, ascorbate is rapidly oxidized by the direct reaction with O 2- ∙ and OH∙ so that OH∙ production eventually becomes completely dependant on O 2 - ∙.[6] The antioxidant property of ascorbic acid in neutralizing effects of OH∙ on biomolecules makes the generation of OH∙ by the ascorbate-iron-H 2 O 2 system less damaging than the OH∙ generation by the O 2 ∙ - -iron-H 2 O 2 system. [2],[7]


  Iron-Mediated Hydroxyl Radical Production in vivo Top


Lactoferrin and transferrin

Earlier reports claimed that iron loaded in lactoferrin and transferrin is an efficient catalyst for OH. radical formation from O 2- ∙ and H 2 O 2 . This finding now has been disproved since the action of OH∙ radical is site specific. In this case, it would have damaged the protein itself. Iron possibly becomes detached from the protein under certain conditions such as the presence of reducing agents and low pH, and the released iron ions are the catalysts for the observed OH∙ radical production. [2]

Ferritin and hemosiderin

Ferritin is often regarded as a safe storage form of iron, yet it has been shown to stimulate the formation of OH∙ radicals from O 2- ∙ and H 2 O 2 . In the presence of suitable reducing agents such as superoxide and ascorbate, ferritin releases iron in the soluble Fe +2 form, leading to the iron-catalyzed production of OH∙ radicals. Hence, the generation of O 2˙ - and H2 O2 adjacent to the ferritin deposits could cause extensive tissue damage. Although it is more difficult to mobilize iron from hemosiderin as compared to ferritin, O' Connell et al. have shown that hemosiderin iron can also participate in OH∙ generation. [2]

Hemoglobin and myoglobin

Several reports claimed that hemoglobin and myoglobins are catalysts of the Fenton reaction; however, such claims have been based on the non-specific assays for OH∙ formation. Although the reaction of intact hemoglobin and myoglobin molecules with H2 O2 does produce some reactive higher oxidation states of the heme iron, there is no clear evidence that these proteins react with H2 O2 to form OH∙ that can be detected outside the protein. However, the incubation of heme proteins with a molar excess of H2 O2 can cause heme degradation and release of iron, which can participate in Fenton reaction to produce OH∙ radical. This may be the possible reason for compartmentalizing hemoglobin in erythrocytes that have high activities of antioxidant enzyme. [2]

Importance of iron in lipid peroxidation

Ferric or ferrous ions by Fenton chemistry yield OH. radicals and initiates lipid peroxidation by abstracting H atom from fatty acids. [2] The role played by ferryl and perferryl species at present are not completely understood. They are definitely less reactive as compared to OH. radicals. [6] The lipid hydroperoxide (ROOH) is unstable in the presence of Fe or other metal catalysts. A reduced iron complex reacts with lipid peroxide and causes the fission of O-O bonds to form alkoxyl radicals (RO). [2],[6]

R-OOH + Fe +2 -Complex →Fe +3 -complex + OH - +R-O∙

An iron complex can form both peroxyl (RO2) and alkoxyl radicals (RO)

R-OOH + Fe +3 -Complex →RO2 + Fe +2 -Complex

Fe +2 -Complex + ROOH →Fe +3 -Complex + OH - +R-O

The reaction of Fe +2 with lipid hydroperoxides is faster than its reaction with H2 O2 and the reactions of Fe +3 with hydroperoxide seem to be considerably slower than that of Fe +2 . [2] Aldehydes are always formed on lipid peroxidation, and many of them are biologically active, particularly a class known as the Hydroxyalkenals, 4-hydroxynonenal is a well known member. These compounds can diffuse from the original site and spread oxidative attack on the adjacent tissue membranes. [8] Lipid peroxidation may be enzymatic or nonenzymatic. Peroxidation stimulated by adding Fe +2 , Fe +3 -ascorbate, azo initiators or synthetic hydroperoxides to lipids is often called nonenzymatic lipid peroxidation. [2] In enzymatic lipid peroxidation, the enzymes cyclooxygenase and lipoxygenase catalyze the controlled peroxidation of their fatty acid substrates to give hydroperoxides and endoperoxides that are stereospecific and have important biological functions. [2]


  Simple Iron Chelates Top


There are intracellular small pools of iron that loosely bind to phosphate esters (such as ATP, ADP and GTP), organic acids (such as citrate) and the polar head groups of membrane lipids or to DNA. All these iron complexes are capable of catalyzing Fenton reaction to produce OH. radicals. This catalytically active form of iron is referred as free iron or non-transferrin-bound iron (NTBI) or low molecular weight iron. The term "free iron" refers to iron loosely bound to a variety of biomolecules in such a way that it retains its ability to catalyze the formation of ROS. [9]


  Measurement of Non-Transferrin-Bound Iron (NTBI) Top


For a long time, the dominating method for analysis of NTBI in biological samples has been the bleomycin assay. The method is based on the binding of iron to bleomycin and the ability of this complex to inflict damage to the DNA, thereby resulting in the formation of intensely colored products in a reaction with thiobarbituric acid (TBA). [10] Other methods that are used in the determination of NTBI are high performance liquid chromatography, [11] fluorescence-based assay, [12] atomic absorption spectrophotometry, [13] colorimetry and electrothermal atomic absorption spectroscopy, [14] graphite furnace atomic absorption spectrometry, [15] inductive conductiometric plasma spectroscopy. [16],[17] Spectrophotometric method has been developed for measuring free iron; this method is cheap, rapid and simple. It uses the iron-chelating property of the dye bathophenanthroline disulphonate (BPS) to detect both ferrous and ferric iron in the same sample. [9],[18] The sensitivity and reproducibility of the colorimetric methods were acceptable as compared with the other methods and would be more convenient as a routine laboratory screening assay for NTBI. However, this method can only be utilized in situations where desferrioxamine is not used and when transferrin saturation levels are close to 100%. Only the HPLC-based method is applicable for patients receiving (desferrioxamine) chelation therapy. In some diseases such as hemochromatosis, transferrin may be incompletely saturated. In such cases, to avoid the in vitro donation of iron onto the vacant sites of transferrin, sodium-tris-carbonatocobaltate (III) can be added to block the free iron-binding sites on transferrin. If this step is not taken, an underestimation of NTBI values may occur. [16]


  Sources of Fenton-Reactive Iron in vivo Top


During evolution, organisms have taken great care in the handling of iron, compartmentalizing iron safely in transport and storage proteins such as transferrin and ferritin, respectively, thereby minimizing the size of the intracellular iron pool. In fact, this kind of iron sequestration is regarded as a contribution to antioxidant defenses. However, oxidant stress can itself provide the iron that is necessary for Fenton chemistry by mobilizing iron from ferritin, transferrin or by degrading heme proteins to release iron. [2]

Under normal conditions, only a minute quantity (less than 3 µmol/L) of intracellular iron is present in a low molecular weight pool , which is bound to weak chelators such as ATP and citrate. However, under appropriate redox conditions, iron is mobilized out of sequestering proteins and participates in Fenton reaction to catalyze hydroxyl (˙OH∙) formation. Reducing agents such as superoxide, ascorbate, reduced flavins, thiols, NADPH-reducing radicals that are generated by redox cycling drugs such as paraquat, adriamycin and alloxan radicals can reduce the Fe +3 ions in ferritin to Fe +2 . Fe +2 is more soluble than Fe +3 and thus can be released from the core of the ferritin molecule. This iron can then participate in oxidation reactions. [5],[7],[19],[20] This makes ferritin a potentially hazardous biomolecule under pathological conditions when sufficient reducing equivalents are available. [19] Similarly, the iron in transferrin can become available for oxidation reactions; however, it appears that this happens only when there is damage to the protein. [7]

Cherng-Tarng et al. reported the use of ascorbic acid as an adjuvant with rHuEPO in chronic renal failure patients on hemodialysis with hyperferritinemia; [21],[22] this could potentiate the mobilization of iron from inert tissue stores and facilitate the incorporation of iron into protoporphyrin in iron-overloaded hemodialysis patients treated with recombinant human erythropoietin. [21] In such cases, ascorbic acid may cause the release of free iron by providing redox conditions. The released iron can undergo the Haber-Weiss reaction to generate ROS and cause damage to the biomolecules. It has been proposed that intravenous iron administration may contribute to carotid atherosclerosis and adverse cardiovascular outcomes in dialysis patients. [23],[24],[25] In addition, the administration of intravenous iron induces protein oxidation. [23],[26] Iron is rapidly incorporated into transferrin and ferritin for iron transport and storage. Intravenous iron supplementation in large doses may potentially exceed the storage capacity and lead to the presence of NTBI in plasma. [2],[27] Approximately 2-6% of total iron in commonly used intravenous iron compounds is available for in vitro iron donation to transferrin. This fraction may contribute to the evidence of bioactive iron in patients after intravenous iron administration. [28]

Non-transferrin-bound iron has generally been detected in disorders with iron overload conditions, such as thalassemia, hemochromatosis and chelation therapy and iron supplementation. NTBI has also been detected in patients undergoing high-dose chemotherapy, particularly those treated with myeloablative therapy and stem cell transplantation. [29],[30],[31],[32],[33] It has been observed that chronic renal failure patients who have received intravenous iron had higher NTBI levels as detected by the BPS assay. [23],[26] It has also been reported that dialysis patients who have nor received iron supplementation also shown an increase in the amount of NTBI as compared to non dialysis CKD patients and normal controls. [34] Authors speculated that besides intravenous iron supplementation, there is some other associated disturbances in hemodialysis process that causes raised NTBI levels in the serum. It may be the hemodialysis procedure per se or may be dialysis related hemolysis. [34] There is increasing epidemiological evidence showing iron overload as a risk factor in chronic renal failure; however, direct evidence is still difficult to obtain. The precise role of iron is complicated further by the complex inter-relationships between iron metabolism and the inflammatory process characteristics of chronic renal failure. The recent discovery of the antimicrobial peptide, hepcidin, may shed light on these interrelationships. [35]

A recent study has shown that the presence of NTBI in chronic renal failure patients on hemodialysis depends on different iron formulations; iron sucrose and sodium ferric gluconate were associated with increased appearance of NTBI as compared with iron dextran. However, only sodium ferric gluconate showed significant increase in lipid peroxidation. The relationship between NTBI from intravenous iron and oxidative stress warrants further exploration. [36],[37] Schaller et al . reported that 300 mg intravenous iron sucrose has a vasodilatory effect; however, it does not impair vascular reactivity in dialysis patients despite a significant increase in NTBI or redox-active iron. [38] In recent years, NTBI has been detected in type 2 diabetic patients with a strong gradient and severity; [10] in hemodialysis patients, higher lipid peroxidation is determined by higher body iron stores and the increase in lipid peroxidation was induced by iron infusion. This is accompanied by a loss in the iron-binding antioxidant capacity and it was more pronounced in diabetes mellitus. [39]

Barton et al . found that dosage of 100 mg of iron sucrose is associated with the presence of NTBI and enhanced Staphylococcus aureus growth. [40] A study by McNamara et al . shows an independent correlation between NTBI and elevated liver function tests, indicating a pathway that leads to hepatic injury; [41] similar findings were obtained by Harrison et al . in long term survivors of acute leukemia and bone marrow transplantation. [42] Van Vlierberghe et al . reported no increase in NTBI in untreated and chronic hepatitis C patients treated with ribavirin; however, the NTBI levels were only higher than normal in hepatitis C patients with higher serum iron levels. [43] De Feo et al . found increased levels of NTBI in active alcohol abusers as compared to those abstained from alcohol and healthy controls. [44] Hirano et al . reported a significant increase in plasma NTBI in preterm infants after blood transfusion and NTBI existed partly in the ferrous form because of the low ferroxidase activity and the reduction of ferric iron (Fe 3+ ) by ascorbic acid. This finding was specific to preterm infants and was not observed in full-term infants after blood transfusion. [45] Mateos et al . reported increased levels of NTBI in patients with Pneumocystis carinii pneumonia. [46]

Hider HC reported recently that NTBI is present in the serum of patients suffering from a wide range of disease states and may be induced under certain therapeutic modalities. However, the chemical nature of this NTBI pool is not clear; however, it is a multicomponent pool that contains a considerable proportion of protein-bound iron. [47] Serum albumin is demonstrated to bind ferric iron even when transferrin is not fully saturated. At present, the nature of NTBI is not clear and it may exist in a number of isoforms. The proportion of these isoforms may depend on the nature of the disease. It is proposed that the different isoforms would be cleared at different rates. It is also speculated that some isoforms would be Fenton active and others lack such activity. [26] Whether the NTBI in vivo is catalytically active [48],[49] or inactive is not clearly elucidated. [34],[50] Free iron is toxic to hematopoietic progenitors in in vitro cultures, and the toxic effect could be reduced with apotransferrin. [51]

Gafter-Gvili et al . [52] found prompt decrease in NTBI following vitamin B12 therapy to pernicious anemia patients, which implicates catabolic iron derived from ineffective erythropoiesis as the major source of NTBI in untreated pernicious anemia and possibly in thalassemia major and sideroblastic anemia. The findings provide insight into the pathogenesis of NTBI in diseases associated with abnormal erythropoiesis. [52] Excess body iron, reflected by elevated serum ferritin and NTBI and decreased total iron binding capacity, was shown to be associated with increased plasma level of soluble intracellular adhesion molecule-1 but not with markers of in vivo LDL oxidation. [53] The exact source of NTBI is not known as NTBI was found to be increased in both the conditions of iron overload [54] and ESRD patients with [26],[55],[56] and without [34] IV iron supplementation. The role of NTBI as a coronary risk factor is also not conclusive; a recent study shows no excess risk of coronary heart disease or acute myocardial infarction within the highest NTBI levels as compared with the lowest; however, it seems to demonstrate a decreased risk. [57]

 
  References Top

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