Non transferrin bound iron: Nature, manifestations and analytical approaches for estimation

Indian Journal of Clinical Biochemistry

Volumn 27, Issue 4, 2012, Pages 322-332

  Patel, Meghna ^a   Ramavataram, D V S S ^b  

^a Institute of Medical Technology   (India)

^b Surat Municipal Institute of Medical Education & Research   (India)

Author keywords

Apo transferrin; Fenton chemistry; Haber Weiss reaction; Non transferrin bound iron; Oxidative stress; Transferrin

Indexed keywords

APO TRANSFERRIN; BLEOMYCIN; CARRIER PROTEIN; DEFEROXAMINE; FERRIC ION; FERRITIN; IRON; IRON BINDING PROTEIN; MALONALDEHYDE; NON TRANSFERRIN BOUND IRON; OXYGEN RADICAL; TRANSFERRIN; UNCLASSIFIED DRUG;

AEROBIC METABOLISM; CARDIOVASCULAR RISK; CHROMATOGRAPHY; COLORIMETRY; DIABETES MELLITUS; ERYTHROID CELL; FENTON REACTION; FLUOROMETRY; HEART DISEASE; HEMATOPOIESIS; HEMOCHROMATOSIS; HEMOLYSIS; HEMOLYTIC ANEMIA; HUMAN; IRON ABSORPTION; IRON BLOOD LEVEL; IRON CHELATION; IRON INTAKE; IRON OVERLOAD; IRON STORAGE; IRON TRANSPORT; KIDNEY INJURY; OXIDATIVE STRESS; REVIEW; THALASSEMIA;

EID: 84867854484     PISSN: 09701915     EISSN: 09740422     Source Type: Journal    
DOI: 10.1007/s12291-012-0250-7     Document Type: Review

References (115)

1. Hider RC. Nature of nontransferrin-bound iron. Eur J Clin Invest. 2002;32:50-4.
2. Hershko H, Graham G, Bates GW, Rachmilewitz E. Nonspecific serum iron in thalassaemia: an abnormal serum iron fraction of potential toxicity. Br J Haematol. 1978;40:255-63.
3. Paffetti P, Perrone S, Longini M, Ferrari A, Tanganelli D, Marzocchi B, et al. Non-protein-bound iron detection in small samples of biological fluids and tissues. Biol Trace Elem Res. 2006;112:221-32.
4. Breuer W, Cabantchik ZI. A fluorescence-based one-step assay for serum non-transferrin-bound iron. Anal Biochem. 2001;299:194-202.
5. Nilsson UA, Bassen M, Sävman K, Kjellmer I. A simple and rapid method for the determination of free iron in biological fluids. Free Radic Res. 2002;36:677-84.
6. Breuer W, Hershko C, Cabantchik ZI. The importance of non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23:185-92.
7. Kruszewski M. Labile iron pool: the main determinant of cellular response to oxidative stress. Mutat Res. 2003;531:81-92.
8. Halliwell B, Gutteridge JM. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol. 1990;186:1-85.
9. Kakhlon O, Cabantchik ZI. The labile iron pool: characterization, measurement, and participation in cellular processes. Free Rad Biol Med. 2002;33:1037-46.
10. von Bonsdorff L, Lindeberg E, Sahlstedt L, Lehto J, Parkkinen J. Bleomycin-detectable iron assay for non-transferrin-bound iron in hematologic malignancies. Clin Chem. 2002;48:307-14.
11. Breuer W, Ermers MJ, Pootrakul P, Abramov A, Hershko C, Cabantchik ZI. Desferrioxamine-chelatable iron, a component of serum non-transferrin-bound iron used for assessing chelation therapy. Blood. 2001;97:792-8.
12. Esposito BP, Breuer W, Sirankapracha P, Pootrakul P, Hershko C, Cabantchik ZI. Labile plasma iron in iron overload: redox activity and susceptibility to chelation. Blood. 2003;102(7):2670-7.
13. Anderson GJ. Non-transferrin-bound iron and cellular toxicity. J Gastroenterol Hepatol. 1999;14(2):105-8.
14. Graham G, Bates GW, Rachmilewitz EA, Hershko C. Non-specific serum iron in thalassaemia: quantitation and chemical reactivity. Am J Hematol. 1979;6:207-17.
15. Porter JB, Abeysinghe RD, Marshall L, Hider RC, Singh S. Kinetics of removal and reappearance of nontransferrin-bound plasma iron with deferoxamine therapy. Blood. 1996;88:705-13.
16. Batey RG, Lai Chung Fong P, Shamir S, Sherlock S. A non-transferrin-bound serum iron in idiopathic hemochromatosis. Dig Dis Sci. 1980;25:340-6.
17. Aruoma OI, Bomford A, Polson RJ, Halliwell B. Nontransferrin-bound iron in plasma from hemochromatosis patients: effect of phlebotomy therapy. Blood. 1988;72:1416-9.
18. Loreal O, Gosriwatana I, Guyader D, Porter J, Brissot P, Hider RC. Determination of non-transferrin-bound iron in genetic hemochromatosis using a new HPLC-based method. J Hepatol. 2000;32:727-33.
19. Gosriwatana I, Loréal O, Lu S, Brissot P, Porter J, Hider RC. Quantification of non-transferrin-bound iron in the presence of unsaturated transferrin. Anal Biochem. 1999;273:212-20.
20. Breuer W, Ronson A, Slotki IN, Abramov A, Hershko C, Cabantchik ZI. The assessment of serum nontransferrin-bound iron in chelation therapy and iron supplementation. Blood. 2000;95:2975-82.
21. al-Refaie FN, Wickens DG, Wonke B, Kontoghiorghes GJ, Hoffbrand AV. Serum non-transferrin-bound iron in beta-thalassaemia major patients treated with desferrioxamine and L1. Br J Haematol. 1992;82:431-6.
22. Lee DH, Liu DY, Jacob DR, Hai-Rim Shin JR, Song K, Lee I, et al. Common presence of non-transferrin-bound iron among patients with type 2 diabetes. Diabetes Care. 2006;29:1090-5.
23. Qian M, Liu M, Eaton JW. Transition metals bind to glycated proteins forming redox active glycochelates: implications for the pathogenesis of certain diabetic complications. Biochem Biophys Res Commun. 1998;250:385-9.
24. Halliwell B, Aruoma OI, Mufti G, Bomford A. Bleomycin-detectable iron in serum from leukaemic patients before and after chemtherapy. Therapeutic implications for treatment with oxidant-generating drugs. FEBS Lett. 1988;241:202-4.
25. Carmine TC, Evans P, Bruchelt G, Evans R, Handretinger R, Niethammer D, et al. Presence of iron catalytic for free radical reactions in patients undergoing chemtherapy: implications for therapeutic management. Cancer Lett. 1995;94:219-26.
26. Dürken M, Nielsen P, Knobel S, Finckh B, Herrnring C, Dresow B, et al. Non-transferrin-bound iron in serum of patients receiving bone marrow transplants. Free Rad Biol Med. 1997;22:1159-63.
27. Bradley SJ, Gosriwatana I, Srichairatanakool S, Hider RC, Porter JB. Non-transferrin-bound iron induced by myeloablative chemtherapy. Br J Haematol. 1997;99:337-43.
28. Lele S, Shah S, McCullough PA, Rajapurkar M. Serum catalytic iron as a novel biomarker of vascular injury in acute coronary syndromes. EuroIntervention. 2009;5:1-7.
29. Harrison-Findik DD, Klein E, Crist C, Evans J, Timchenko N, Gollan J. Iron-mediated regulation of liver hepcidin expression in rats and mice is abolished by alcohol. Hepatology. 2007;46:1979-85.
30. Detivaud L, Nemeth E, Boudjema K, Turlin B, Troadec MB, Leroyer P, et al. Hepcidin levels in humans are correlated with hepatic iron stores, hemoglobin levels, and hepatic function. Blood. 2005;106:746-8.
31. De Feo TM, Fargion S, Duca L, Cesana BM, Boncinelli L, Lozza P, et al. Non-transferrin-bound iron in alcohol abusers. Alcohol Clin Exp Res. 2001;25:1494-9.
32. Cortelezzi A, Cattaneo C, Cristiani S, Duca L, Sarina B, Deliliers GL, et al. Non-transferrin-bound iron in myelodysplastic syndromes: A marker of ineffective erythropoiesis? Hematol J. 2000;1:153-8.
33. Mahesh S, Ginzburg Y, Verma A. Iron overload in myelodysplastic syndromes. Leuk Lymphoma. 2008;49:427-38.
34. Brazzolotto X, Gaillard J, Pantopoulos K, Hentze MW, Moulis JM. Human cytoplasmic aconitase (iron regulatory protein 1) is converted into its [3Fe-4S] form by hydrogen peroxide in vitro but is not activated for iron-responsive element binding. J Biol Chem. 1999;274:21625-30.
35. Halliwell B. Free radicals and antioxidants: a personal view. Nutr Rev. 1994;52:253-65.
36. Halliwell B. The role of oxygen radicals in human disease, with particular reference to the vascular system. Haemostasis. 1993;23(suppl 1):118-26.
37. Biemond P, Van Eijk HG, Swaak AJG, Koster JF. Iron mobilization from ferritin by superoxide derived from stimulated polymorphonuclear leukocytes: possible mechanism in inflammatory diseases. J Clin Invest. 1984;73:1576-9.
38. Abdalla DS, Campa A, Monteiro HP. Low density lipoprotein oxidation by stimulated neutrophils and ferritin. Atherosclerosis. 1992;97:149-59.
39. Gutteridge JMC. Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett. 1986;201:291-5.
40. Puppo A, Halliwell B. Formation of hydroxyl radicals from hydrogen peroxide in the presence of iron: Is haemoglobin a biological Fenton catalyst? Biochem J. 1988;249:185-90.
41. Gutteridge JMC, Smith A. Antioxidant protection by haemopexin of haemstimulated lipid peroxidation. Biochem J. 1988;256:861-5.
42. Balla G, Jacob HS, Eaton JW, Belcher JD, Vercellotti GM. Hemin: a possible physiological mediator of low density lipoprotein oxidation and endothelial injury. Arterioscler Thromb. 1991;11:1700-11.
43. Le Lan C, Loréal O, Cohen T, Ropert M, Glickstein H, Lainé F, et al. Redox active plasma iron in C282Y/C282Y hemochromatosis. Blood. 2005;105:4527-31.
44. Sharma M, Saxena R, Gohil NK. Fluorescence assay of non-transferrin-bound iron in thalassemic sera using bacterial siderophore. Anal Biochem. 2009;394:186-91.
45. Weijl NI, Elsendoorn TJ, Moison RM, Lentjes EG, Brand R, Berger HM, et al. Non-protein bound iron release during chemotherapy in cancer patients. Clin Sci (Lond). 2004;106:475-84.
46. Grootveld M, Bell JD, Halliwell B, Aruoma OI, Bomford A, Sadler PJ. Non-transferrin bound iron in plasma or serum from patients with idiopathic hemochromatosis. J Biol Chem. 1989;264:4417-22.
47. Lovstad RA. Interaction of serum albumin with the Fe(III)-citrate complex. Int J Biochem. 1993;25:1015-7.
48. May PM, Williams DR. Computer simulation of chelation therapy. Plasma mobilizing index as a replacement for effective stability constant. FEBS Lett. 1977;78:134-8.
49. van der Heul C, van Eijk HG, Wiltink WF, Leijnse B. The binding of iron to transferrin and to other serum components at different degrees of saturation with iron. Clin Chim Acta. 1972;38:347-53.
50. Pootrakul P, Sirankapracha P, Sankote J, Kachintorn U, Maungsub W, Sriphen K, et al. Clinical trial of deferiprone iron chelation therapy in beta-thalassaemia/haemoglobin E patients in Thailand. Br J Haematol. 2003;122:305-10.
51. Pootrakul P, Breuer W, Sametband M, Sirankapracha P, Hershko C, Cabantchik ZI. Labile plasma iron (LPI) as an indicator of chelatable plasma redox activity in iron-overloaded b-thalassemia/HbE patients treated with an oral chelator. Blood. 2004;104:1504-10.
52. Gutteridge JMC, Rowley DA, Halliwell B. Superoxide-dependent formation of hydroxyl radicals I in the presence of iron salts. Biochem J. 1981;199:263-5.
53. Gutteridge JMC, Halliwell B. Radical promoting loosely-bound iron in biological fluids and the bleomycin assay. Life Chem Rep. 1987;4:113-42.
54. Evans PJ, Halliwell B. Measurement of iron and copper in biological systems: bleomycin and copper-phenanthroline assays. Methods Enzymol. 1994;233:82-92.
55. Sahlstedt L, Ebeling F, von Bonsdorff L, Parkkinen J, Ruutu T. Non-transferrin-bound iron during allogeneic stem cell transplantation. Br J Haematol. 2001;113:836-8.
56. Burkitt MJ, Milne L, Raafat A. A simple, highly sensitive and improved method for the measurement of bleomycin-detectable iron: the 'catalytic iron index' and its value in the assessment of iron status in haemochromatosis. Clin Sci. 2001;100:239-47.
57. Han KE, Okada S. Serum bleomycin detectable iron in patients with thalassemia major with normal range of serum iron. Acta Med Okayama. 1995;49:117-21.
58. Shah SV. Oxidants and iron in chronic kidney disease. Kidney Int Suppl. 2004;91:50-5.
59. Evans PJ, Evans R, Kovar IZ, Holton AF, Halliwell B. Bleomycin-detectable iron in the plasma of premature and full-term neonates. FEBS Lett. 1992;303:210-2.
60. Gutteridge JMC. Ferrous ions detected in cerebrospinal fluid by using bleomycin and DNA damage. Clin Sci. 1992;82:315-20.
61. Esposito BP, Breuer W, Slotki I, Cabantchik ZI. Labile iron in parenteral iron formulations and its potential for generating plasma nontransferrin-bound iron in dialysis patients. Eur J Clin Invest. 2002;32:42-9.
62. Singh S, Hider RC, Porter JB. A direct method for quantification of non-transferrin-bound iron. Anal Biochem. 1990;186:320-3.
63. Kolb AM, Smit NP, Lentz-Ljuboje R, Osanto S, van Pelt J. Non-transferrin bound iron measurement is influenced by chelator concentration. Anal Biochem. 2009;385:13-9.
64. Jacobs EM, Hendriks JC, van Tits BL, Evans PJ, Breuer W, Liu DY, et al. Results of an international round robin for the quantification of serum non-transferrin-bound iron: need for defining standardization and a clinically relevant isoform. Anal Biochem. 2005;341:241-50.
65. Zhang D, Okada S, Kawabata T, Yasuda T. An improved simple colorimetric method for quantification of non-transferrin-bound iron in serum. Biochem Mol Biol Int. 1995;35:635-41.
66. Collins KE, Collins CH, Bertran CA, Dolan J. Stainless steel surfaces in LC systems, Part 1-corrosion and erosion. LC GC Int. 2000;13:464-70.
67. Sasaki K, Ikuta K, Tanaka H, Ohtake T, Torimoto Y, Fujiya M, et al. Improved quantification for non-transferrin-bound iron measurement using high-performance liquid chromatography by reducing iron contamination. Mol Med Rep. 2011;4:913-8.
68. Jittangprasert P, Wilairat P, Pootrakul P. Comparison of colorimetry and electrothermal atomic absorption spectroscopy for the quantification of non-transferrin bound iron in human sera. Southeast Asian J Trop Med Public Health. 2004;35:1039-44.
69. Sharma M, Gohil NK. Interaction of azotobactin with blocking and mobilizing agents in NTBI assay. Mol BioSyst. 2010;6:1941-6.
70. Chau L. Iron and atherosclerosis. Proceedings of the national science council, Republic of ChinaPart B. Life Sci. 2000;24:151-5.
71. Meyers DG. The iron hypothesis: Does iron play a role in atherosclerosis? Transfusion. 2000;40:1023-9.
72. Gackowski D, Kruszewski M, Jawien A, Ciecierski M, Olinski R. Further evidence that oxidative stress may be a risk factor responsible for the development of atherosclerosis. Free Radic Biol Med. 2001;31:542-7.
73. Mohan S, Kalia K, Mannari J. Diabetic nephropathy and associated risk factors for renal deterioration. Int J diabetes Dev Ctries. 2011;32:52-9.
74. Horwitz L, Rosenthal E. Iron-mediated cardiovascular injury. Vasc Med. 1999;4:93-9.
75. Pai B, Pai MP, Depczynski J, McQuade CR, Mercier RC. Nontransferrin-bound iron is associated with enhanced Staphylococcus aureus growth in hemodialysis patients receiving intravenous iron sucrose. Am J Nephrol. 2006;26:304-9.
76. Cabantchik ZI, Breuer W, Zanninelli G, Cianciulli P. LPI-labile plasma iron in iron overload. Best Pract Res Clin Haematol. 2005;18:277-87.
77. Koppenol WH. The Haber-Weiss cycle70 years later. Redox Rep. 2001;6:229-34.
78. Fridovich I. Oxygen toxicity: a radical explanation. J Exp Biol. 1998;201:1203-9.
79. - in mediating the toxicity of O•. Free Radic Biol Med. 1999;26:777-8.
80. Termini J. Hydroperoxide-induced DNA. Damage and mutations. Mutat Res. 2000;450:107-24.
81. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet. 1981;1:1293-4.
82. Schafer AI, Cheron RG, Dluhy R, Cooper B, Gleason RE, Soeldner JS, et al. Clinical consequences of acquired transfusional iron overload in adults. N Engl J Med. 1981;304:319-24.
83. Ascherio A, Willett WC, Rimm EB, Giovannucci EL, Stampfer MJ. Dietary iron intake and risk of coronary disease among men. Circulation. 1994;89:969-74.
84. Lee DH, Folsom AR, Jacobs DRJ. Iron, zinc, and alcohol consumption and mortality from cardiovascular diseases: the Iowa Women's Health Study. Am J Clin Nutr. 2005;81:787-91.
85. van der ADL, Peeters PH, Grobbee DE, Marx JJ, van der Schouw YT. Dietary haem iron and coronary heart disease in women. Eur Heart J. 2005;26:257-62.
86. Ramakrishnan U, Kuklina E, Stein AD. Iron stores and cardiovascular disease risk factors in women of reproductive age in the United States. Am J Clin Nutr. 2002;76:1256-60.
87. Ross R. Atherosclerosisan inflammatory disease. N Engl J Med. 1999;340:115-26.
88. Salvemini D, Wang ZQ, Bourdon DM, Stern MK, Currie MG, Manning PT. Evidence of peroxynitrite involvement in the carrageenan-induced rat paw edema. Eur J Pharmacol. 1996;303:217-20.
89. Cuzzocrea S, Zingarelli B, Costantino G, Szabo A, Salzman AL, Caputi AP, et al. Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion. Br J Pharmacol. 1997;121:1065-74.
90. Leake D, Rankin S. The oxidative modi. Cation of low-density lipoproteins by macrophages. Biochem J. 1990;270:741-8.
91. Knight JA. Free radicals, antioxidants, aging and disease. Washington, DC: AACC Press; 1999.
92. Praticó D, Pasin M, Barry OP, Ghiselli A, Sabatino G, Iuliano L, et al. Iron-dependent human platelet activation and hydroxyl radical formation: involvement of protein kinase C. Circulation. 1999;99:3118-24.
93. Oudit GY, Trivieri MG, Khaper N, Husain T, Wilson GJ, Liu P, et al. Taurine supplementation reduces oxidative stress and improves cardiovascular function in an iron-overload murine model. Circulation. 2004;109:1877-85.
94. Voogd A, Sluiter W, Koster JF. The increased susceptibility to hydrogen peroxide of the (post-)ischemic rat heart is associated with the magnitude of the low molecular weight iron pool. Free Radic Biol Med. 1994;16:453-8.
95. Kartikasari AE, Georgiou NA, Visseren FL, van Kats-Renaud H, van Asbeck BS, Marx JJ. Intracellular labile iron modulates adhesion of human monocytes to human endothelial cells. Arterioscler Thromb Vasc Biol. 2004;24:2257-62.
96. Koo SW, Casper KA, Otto KB, Gira AK, Swerlick RA. Iron chelators inhibit VCAM-1 expression in human dermal microvascular endothelial cells. J Invest Dermatol. 2003;120:871-9.
97. Zhang WJ, Frei B. Intracellular metal ion chelators inhibit TNF alpha-induced SP-1 activation and adhesion molecule expression in human aortic endothelial cells. Free Radic Biol Med. 2003;34:674-82.
98. Danesh J, Appleby P. Coronary heart disease and iron status: meta-analyses of prospective studies. Circulation. 1999;99:852-4.
99. Derstine JL, Murray-Kolb LE, Yu-Poth S, Hargrove RL, Kris-Etherton PM, Beard JL. Iron status in association with cardiovascular disease risk in 3 controlled feeding studies. Am J Clin Nutr. 2003;77:56-62.
100. Baer DM, Tekawa IS, Hurley LB. Iron stores are not associated with acute myocardial infarction. Circulation. 1994;89:2915-8.
101. Corti MC, Guralnik JM, Salive ME, Ferrucci L, Pahor M, Wallace RB, et al. Serum iron level, coronary artery disease, and all-cause mortality in older men and women. Am J Cardiol. 1997;79:120-7.
102. Knuiman MW, Divitini ML, Olynyk JK, Cullen DJ, Bartholomew HC. Serum ferritin and cardiovascular disease: a 17-year follow-up study in Busselton Western Australia. Am J Epidemiol. 2003;158:144-9.
103. Sempos CT, Looker AC, Gillum RE, Mc-Gee DL, Vuong CV, Johnson CL. Serum ferritin and death from all causes and cardiovascular disease: the NHANES II Mortality study. Ann Epidemiol. 2000;10:441-8.
104. Andrews NC. The iron transporter DMT 1. Int J Biochem Cell Biol. 1999;31:991-4.
105. Dandona P, Hussain MA, Varghese Z, Politis D, Flynn DM, Hoffbrand AV. Insulin resistance and iron overload. Ann Clin Biochem. 1983;20:77-9.
106. Mendler MH, Turlin B, Moirand R, Jouanolle AM, Sapey T, Guyader D, et al. Insulin resistance-associated hepatic iron overload. Gastroenterology. 1999;117:1155-63.
107. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44:129-46.
108. Jackson P, Loughrey CM, Lightbody JH, McNamee PT, Young IS. Effect of hemodialysis on total antioxidant capacity and serum antioxidants in patients with chronic renal failure. Clin Chem. 1995;41:1135-8.
109. Redmon JB, Pyzdrowski KL, Robertson RP. No effect of deferoxamine therapy on glucose homeostasis and insulin secretion in individuals with NIDDM and elevated serum ferritin. Diabetes. 1993;42:544-9.
110. Nankivell BJ, Boadle RA, Harris DCH. Iron accumulation in human chronic renal disease. Am J Kidney Dis. 1992;20:580-4.
111. Shah SV, Baliga R, Rajapurkar M, Fonseca VA. Oxidants in chronic kidney disease. J Am Soc Nephrol. 2007;18:16-28.
112. Descamps-Latscha B, Witko-Sarsat V, Nguyen-Khoa T, Nguyen AT, Gausson V, Mothu V, et al. Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers. Kidney Int. 2004;66:1606-12.
113. Lin JL, LinTan DT, Hsu KH, Yu CC. Environmental lead exposure and progression of chronic renal diseases in patients without diabetes. N Engl J Med. 2003;348:277-86.
114. Prus E, Fibach E. Uptake of non-transferrin iron by erythroid cells. Anemia. 2011;2011 (Article ID 945289, 8 pages).
115. Loken MR, Shah VO, Dattilio KL, Civin CI. Flow cytometric analysis of human bone marrow II. Normal B lymphocyte development. Blood. 1987;70:1316-24.