Iron Toxicity and Chelation Therapy

Abstract

Iron is an essential mineral for normal cellular physiology, but an excess can result in cell injury. Iron in low-molecular-weight forms may play a catalytic role in the initiation of free radical reactions. The resulting oxyradicals have the potential to damage cellular lipids, nucleic acids, proteins, and carbohydrates; the result is wide-ranging impairment in cellular function and integrity. The rate of free radical production must overwhelm the cytoprotective defenses of cells before injury occurs. There is substantial evidence that iron overload in experimental animals can result in oxidative damage to lipids in vivo, once the concentration of iron exceeds a threshold level. In the liver, this lipid peroxidation is associated with impairment of membrane-dependent functions of mitochondria and lysosomes. Iron overload impairs hepatic mitochondrial respiration primarily through a decrease in cytochrome C oxidase activity, and hepatocellular calcium homeostasis may be compromised through damage to mitochondrial and microsomal calcium sequestration. DNA has also been reported to be a target of iron-induced damage, and this may have consequences in regard to malignant transformation. Mitochondrial respiratory enzymes and plasma membrane enzymes such as sodium-potassium-adenosine triphosphatase (Na++K+-ATPase) may be key targets of damage by non-transferrin-bound iron in cardiac myocytes. Levels of some antioxidants are decreased during iron overload, a finding suggestive of ongoing oxidative stress. Reduced cellular levels of ATP, lysosomal fragility, impaired cellular calcium homeostasis, and damage to DNA all may contribute to cellular injury in iron overload. Evidence is accumulating that free-radical production is increased in patients with iron overload. Iron-loaded patients have elevated plasma levels of thiobarbituric acid reactants and increased hepatic levels of aldehyde-protein adducts, indicating lipid peroxidation. Hepatic DNA of iron-loaded patients shows evidence of damage, including mutations of the tumor suppressor gene p53. Although phlebotomy therapy is effective in removing excess iron in hereditary hemochromatosis, chelation therapy is required in the treatment of many patients who have combined secondary and transfusional iron overload due to disorders in erythropoiesis. In patients with β-thalassemia who undergo regular transfusions, deferoxamine treatment has been shown to be effective in preventing iron-induced tissue injury and in prolonging life expectancy. The use of the oral chelator deferiprone remains controversial, and work is continuing on the development of new orally effective iron chelators.

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References

  1. 1.

    Bacon BR. Hemochromatosis: diagnosis and management.Gastroenterology. 2001;120:718–725.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Powell LW. Hereditary hemochromatosis and iron overload diseases.J Gastroenterol Hepatol. 2002;17(suppl 1):191–195.

    Article  Google Scholar 

  3. 3.

    Bacon BR, Tavill AS. Hemochromatosis and the iron overload syndromes. In: Zakim D, Boyer TD, eds.Hepatology: A Textbook of Liver Disease. 3rd ed. Philadelphia: WB Saunders; 1996:1439–1472.

    Google Scholar 

  4. 4.

    Bottomley SS. Secondary iron overload disorders.Semin Hematol. 1998;35:77–86.

    PubMed  CAS  Google Scholar 

  5. 5.

    Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH. Molecular medicine and hemochromatosis: at the crossroads.Gastroenterology. 1999;116:193–207.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  6. 6.

    Britton RS. Metal-induced hepatotoxicity.Semin Liver Dis. 1996;16:3–12.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Okada S. Iron-induced tissue damage and cancer: the role of reactive oxygen species-free radicals.Pathol Int. 1996;46:311–332.

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    Toyokuni S. Iron-induced carcinogenesis: the role of redox regulation.Free Radic Biol Med. 1996;20:553–566.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Pietrangelo A. Metals, oxidative stress, and hepatic fibrogenesis.Semin Liver Dis. 1996;16:13–30.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Hershko C, Link G, Cabantchik I. Pathophysiology of iron overload.Ann N Y Acad Sci. 1998;850:191–201.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Bonkovsky HL, Lambrecht RW. Iron-induced liver injury.Clin Liver Dis. 2000;4:409–429.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Welch KD, Davis TZ, Van Eden ME, Aust SD. Deleterious iron-mediated oxidation of biomolecules.Free Radic Biol Med. 2002;32:577–583.

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Eaton JW, Qian M. Molecular bases of cellular iron toxicity.Free Radic Biol Med. 2002;32:833–840.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Hershko C, Konijn AM, Link G. Iron chelators for thalassaemia.Br J Haematol. 1998;101:399–406.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Kushner JP, Porter JP, Olivieri NF. Secondary iron overload.Hematology (Am Soc Hematol Educ Program). 2001;Jan:47–61.

  16. 16.

    Giardina PJ, Grady RW. Chelation therapy in β-thalassemia: an optimistic update.Semin Hematol. 2001;38:360–366.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Halliwell B, Gutteridge JMC.Free Radicals in Biology and Medicine. 3rd ed. Oxford: Oxford University Press; 1999.

    Google Scholar 

  18. 18.

    Burkitt MJ, Mason RP. Direct evidence forin vivo hydroxyl-radical generation in experimental iron overload: an ESR spin-trapping investigation.Proc Natl Acad Sci U S A. 1991;88:8440–8444.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  19. 19.

    Kadiiska MB, Burkitt MJ, Xiang Q-U, Mason RP. Iron supplementation generates hydroxyl radicalin vivo: an ESR spin-trapping study.J Clin Invest. 1995;96:1653–1657.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Bacon BR, Tavill AS, Brittenham GM, Park CH, Recknagel RO. Hepatic lipid peroxidationin vivo in rats with chronic iron overload.J Clin Invest. 1983;71:429–439.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  21. 21.

    Bacon BR, Brittenham GM, Tavill AS, McLaren CE, Park CH, Recknagel RO. Hepatic lipid peroxidationin vivo in rats with chronic dietary iron overload is dependent on hepatic iron concentration.Trans Assoc Am Phys. 1983;96:146–154.

    PubMed  CAS  Google Scholar 

  22. 22.

    Bacon BR, Britton RS. The pathology of hepatic iron overload: a free radical-mediated process?Hepatology. 1990;11:127–137.

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    Sies H, Stahl W. Vitamins E and C, β-carotene, and other carotenoids as antioxidants.Am J Clin Nutr. 1995;62:1315S-1321S.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Dabbagh AJ, Mannion T, Lynch SM, Frei B. The effect of iron overload on rat plasma and liver oxidant statusin vivo.Biochem J. 1994;300:799–803.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  25. 25.

    Dresow B, Albert C, Zimmermann I, Nielsen P. Ethane exhalation and vitamin E/ubiquinol status as markers of lipid peroxidation in ferrocene iron-loaded rats.Hepatology. 1995;21:1099–1105.

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Brown KE, Kinter MT, Oberley TD, et al. Enhanced γ-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload.Free Radic Biol Med. 1998;24:545–555.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Young IS, Trouton TG, Torney JJ, McMaster D, Callender ME, Trimble ER. Antioxidant status and lipid peroxidation in hereditary haemochromatosis.Free Radic Biol Med. 1994;16:393–397.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    von Herbay A, de Groot H, Hegi U, Stremmel W, Strohmeyer G, Sies H. Low vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson’s disease.J Hepatol. 1994;20:41–46.

    Article  Google Scholar 

  29. 29.

    Niemela O, Parkkila S, Britton RS, Brunt E, Janney C, Bacon BR. Hepatic lipid peroxidation in hereditary hemochromatosis and alcoholic liver injury.J Lab Clin Med. 1999;133:451–460.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Houglum K, Ramm GA, Crawford DHG, Witztum JL, Powell LW, Chojkier M. Excess iron induces hepatic oxidative stress and transforming growth factor β1 in genetic hemochromatosis.Hepatology. 1997;26:605–610.

    PubMed  Article  CAS  Google Scholar 

  31. 31.

    Livrea MA, Tesoriere L, Pintaudi AM, et al. Oxidative stress and antioxidant status in β-thalassemia major: iron overload and depletion of lipid-soluble antioxidants.Blood. 1996;88:3608–3614.

    PubMed  CAS  Google Scholar 

  32. 32.

    Iancu TC, Shiloh H. Morphological observations in iron overload: an update.Adv Exp Med Biol. 1994;356:255–265.

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    LaRusso NF. Hepatic lysosomes in intracellular digestion and biliary secretion. In: Forte JG, ed.Handbook of Physiology: The Gastrointestinal System III. Bethesda: American Physiological Society; 1989:677–691.

    Google Scholar 

  34. 34.

    Peters TJ, Seymour CA. Acid hydrolase activities and lysosomal integrity in liver biopsies from patients with iron overload.Clin Sci Mol Med. 1976;50:75–78.

    PubMed  CAS  Google Scholar 

  35. 35.

    Seymour CA, Peters TJ. Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes.Br J Haematol. 1978;40:239–253.

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Selden C, Owen M, Hopkins JMP, Peters TJ. Studies on the concentration and intracellular localization of iron proteins in liver biopsy specimens from patients with iron overload with special reference to their role in lysosomal disruption.Br J Haematol. 1980;44:593–603.

    PubMed  Article  CAS  Google Scholar 

  37. 37.

    Peters TJ, O’Connell MJ, Ward RJ. Role of free-radical mediated lipid peroxidation in the pathogenesis of hepatic damage by lysosomal disruption. In: Poli G, Cheeseman KH, Dianzani MU, Slater TF, eds.Free Radicals in Liver Injury. Oxford: IRL Press; 1985:107–115.

    Google Scholar 

  38. 38.

    Stål P, Glaumann H, Hultcrantz R. Liver cell damage and lysosomal iron storage in patients with idiopathic hemochromatosis: a light and electron microscopic study.J Hepatol. 1990;11:172–180.

    PubMed  Article  Google Scholar 

  39. 39.

    Frigerio R, Mela Q, Passiu G, et al. Iron overload and lysosomal stability in β-thalassemia intermedia and trait: Correlation between serum ferritin and serumN-acetyl-β-D-glucosaminidase levels.Scand J Haematol. 1984;33:252–255.

    PubMed  Article  CAS  Google Scholar 

  40. 40.

    O’Connell MJ, Ward RJ, Baum H, Peters TJ. The role of iron in ferritin and haemosiderin-mediated lipid peroxidation in lysosomes.Biochem J. 1985;229:135–139.

    PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    O’Connell M, Halliwell B, Moorhouse CP, Aruoma OI, Baum H, Peters TJ. Formation of hydroxyl radicals in the presence of ferritin and haemosiderin: is haemosiderin formation a biological protective mechanism?Biochem J. 1986;234:727–731.

    PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Hultcrantz R, Ahlberg J, Glaumann H. Isolation of two lysosomal populations from iron overloaded rat liver with different iron concentration and proteolytic activity.Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;47:55–65.

    PubMed  Article  CAS  Google Scholar 

  43. 43.

    LeSage GD, Kost LJ, Barham SS, LaRusso NF. Biliary excretion of iron from hepatocyte lysosomes in the rat: a major excretory pathway in experimental iron overload.J Clin Invest. 1986;77:90–97.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  44. 44.

    Myers BM, Prendergast FG, Holman R, Kuntz SM, LaRusso NF. Alterations in the structure, physicochemical properties, and pH of hepatocyte lysosomes in experimental iron overload.J Clin Invest. 1991;88:1207–1215.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    Bacon BR, Park CH, Brittenham GM, O’Neill R, Tavill AS. Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload.Hepatology. 1985;5:789–797.

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    Hultcrantz R, Glaumann H. Studies on the rat liver following iron overload: biochemical analysis after iron mobilization.Lab Invest. 1982;46:383–392.

    PubMed  CAS  Google Scholar 

  47. 47.

    Bacon BR, Britton RS, O’Neill R. Effects of vitamin E deficiency on hepatic mitochondrial lipid peroxidation and oxidative metabolism in rats with chronic dietary iron overload.Hepatology. 1989;9:398–404.

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Bacon BR, O’Neill R, Britton RS. Hepatic mitochondrial energy production in rats with chronic iron overload.Gastroenterology. 1993;105:1134–1140.

    PubMed  Article  CAS  Google Scholar 

  49. 49.

    Bacon BR, O’Neill R, Park CH. Iron-induced peroxidative injury to isolated rat hepatic mitochondria.J Free Radic Biol Med. 1986;2:339–347.

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    Ceccarelli D, Predieri G, Muscatello U, Masini A. A31P-NMR study on the energy state of rat liver in an experimental model of chronic dietary iron overload.Biochem Biophys Res Commun. 1991;176:1262–1268.

    PubMed  Article  CAS  Google Scholar 

  51. 51.

    Pietrangelo A, Borella F, Casalgrandi G, et al. Antioxidant activity of silybinin vivo during long-term iron overload in rats.Gastroenterology. 1995;109:1941–1949.

    PubMed  Article  CAS  Google Scholar 

  52. 52.

    Britton RS, O’Neill R, Bacon BR. Chronic dietary iron overload in rats results in impaired calcium sequestration by hepatic mitochondria and microsomes.Gastroenterology. 1991;101:806–811.

    PubMed  Article  CAS  Google Scholar 

  53. 53.

    Masini A, Ceccarelli D, Trenti T, Corongiu FP, Muscatello U. Perturbation in liver mitochondrial Ca2+ homeostasis in experimental iron overload: a possible factor in cell injury.Biochim Biophys Acta. 1989;1014:133–140.

    PubMed  Article  CAS  Google Scholar 

  54. 54.

    Carafoli E. Intracellular calcium homeostasis.Ann Rev Biochem. 1987;56:395–433.

    PubMed  Article  CAS  Google Scholar 

  55. 55.

    Bacon BR, Healey JF, Brittenham GM, et al. Hepatic microsomal function in rats with chronic dietary iron overload.Gastroenterology. 1986;90:1844–1853.

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Schacter BA, Marver HS, Meyer UA. Hemoprotein catabolism during stimulation of microsomal lipid peroxidation.Biochim Biophys Acta. 1972;279:221–227.

    PubMed  Article  CAS  Google Scholar 

  57. 57.

    Levin W, Lu AYH, Jacobson M, Kuntzman R, Poyer JL, McCay PB. Lipid peroxidation and the degradation of cytochrome P-450 heme.Arch Biochim Biophys. 1973;158:842–853.

    Article  CAS  Google Scholar 

  58. 58.

    Waller RL, Glende Jr EA, Recknagel RO. Carbon tetrachloride and bromotrichloromethane toxicity: dual role of covalent binding of metabolic cleavage products and lipid peroxidation in depression of microsomal calcium sequestration.Biochem Pharmacol. 1983;32:1613–1617.

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    Bonkovsky HL, Mitchell WJ, Healey JF. Effect of hemochromatosis on hepatic cytochrome P450 and antipyrine metabolism in humans.Clin Chem. 1984;30:1430–1431.

    PubMed  CAS  Google Scholar 

  60. 60.

    Link G, Pinson A, Hershko C. Iron loading of cultured cardiac myocytes modifies sarcolemmal structure and increases lysosomal fragility.J Lab Clin Med. 1993;121:127–134.

    PubMed  CAS  Google Scholar 

  61. 61.

    Link G, Pinson A, Hershko C. Identification of thiolic sarcolemmal proteins as a primary target of iron toxicity in cultured heart cells.Adv Exp Med Biol. 1994;356:267–276.

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Link G, Pinson A, Hershko C. Ability of the orally effective iron chelators dimethyl- and diethyl-hydroxypyrid-4-one and of deferoxamine to restore sarcolemmal thiolic enzyme activity in iron-loaded heart cells.Blood. 1994;83:2692–2697.

    PubMed  CAS  Google Scholar 

  63. 63.

    Link G, Saada A, Pinson A, Konijn AM, Hershko C. Mitochondrial respiratory enzymes are a major target of iron toxicity in rat heart cells.J Lab Clin Med. 1998;131:466–474.

    PubMed  Article  CAS  Google Scholar 

  64. 64.

    Link G, Konijn AM, Hershko C. Cardioprotective effect of alpha-tocopherol, ascorbate, deferoxamine, and deferiprone: mitochondrial function in cultured, iron-loaded heart cells.J Lab Clin Med. 1999;133:179–188.

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    Bradbear RA, Bain C, Siskind V, et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases.J Natl Cancer Inst. 1985;75:81–84.

    PubMed  CAS  Google Scholar 

  66. 66.

    Niederau C, Fischer R, Sonnenberg A, Stremmel W, Trampisch HJ, Strohmeyer G. Survival and causes of death in cirrhotic and in non-cirrhotic patients with primary hemochromatosis.N Engl J Med. 1985;313:1256–1262.

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Imlay JA, Chin SM, Linn S. Toxic DNA damage by hydrogen peroxide through the Fenton reactionin vivo andin vitro.Science. 1988;240:640–642.

    PubMed  Article  CAS  Google Scholar 

  68. 68.

    Toyokuni S, Sagripanti JL. Induction of oxidative single- and double-strand breaks in DNA by ferric citrate.Free Radic Biol Med. 1993;15:117–123.

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Hruszkewycz AM. Evidence for mitochondrial DNA damage by lipid peroxidation.Biochem Biophys Res Commun. 1988;153:191–197.

    PubMed  Article  CAS  Google Scholar 

  70. 70.

    Shires TK. Iron-induced DNA damage and synthesis in isolated rat liver nuclei.Biochem J. 1982;205:321–329.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. 71.

    Mello Filho AC, Meneghini R.In vivo formation of single strand breaks in DNA by hydrogen peroxide is mediated by the Haber-Weiss reaction.Biochim Biophys Acta. 1984;781:56–63.

    Article  Google Scholar 

  72. 72.

    Starke PE, Farber JL. Ferric iron and superoxide ions are required for the killing of cultured hepatocytes by hydrogen peroxide: evidence for the participation of hydroxyl radicals formed by an iron-catalyzed Haber-Weiss reaction.J Biol Chem. 1985;260:10099–10104.

    PubMed  CAS  Google Scholar 

  73. 73.

    Halliwell B, Gutteridge JMC. Role of free radicals and catalytic metal ions in human disease: an overview.Methods Enzymol. 1990;186:1–85.

    PubMed  Article  CAS  Google Scholar 

  74. 74.

    Park J-W, Floyd RA. Lipid peroxidation products mediate the formation of 8-hydroxydeoxyguanosine in DNA.Free Radic Biol Med. 1992;12:245–250.

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    Edling JE, Britton RS, Grisham MB, Bacon BR. Increased unwinding of hepatic double-stranded DNA (dsDNA) in rats with chronic dietary iron overload [abstract].Gastroenterology. 1990;98:A585.

    Google Scholar 

  76. 76.

    Walles SAS, Erixson K. Single-strand breaks in DNA of various organs of mice induced by methyl methanesulfonate and dimethyl-sulfoxide determined by the alkaline unwinding technique.Carcinogenesis. 1984;5:319–322.

    Article  CAS  Google Scholar 

  77. 77.

    Hartley JA, Gibson NW, Zwelling LA, Yuspa SH. Association of DNA strand breaks with accelerated terminal differentiation in mouse epidermal cells exposed to tumor promoters.Cancer Res. 1985;45:4864–4870.

    PubMed  CAS  Google Scholar 

  78. 78.

    Walter PB, Knutson MD, Paler-Martinez A, et al. Iron deficiency and iron excess damage mitochondria and mitochondrial DNA in rats.Proc Natl Acad Sci U S A. 2002;99:2264–2269.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  79. 79.

    Faux SP, Francis JE, Smith AG, Chipman JK. Induction of 8-hydroxydeoxyguanosine inAh-responsive mouse liver by iron and Aroclor 1254.Carcinogenesis. 1992;13:247–250.

    PubMed  Article  CAS  Google Scholar 

  80. 80.

    Kang JO, Jones C, Brothwell B. Toxicity associated with iron overload found in hemochromatosis: possible mechanism in a rat model.Clin Lab Sci. 1998;11:350–354.

    PubMed  CAS  Google Scholar 

  81. 81.

    Kuchino Y, Mori F, Kasai H, et al. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues.Nature. 1987;327:77–79.

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    Wood ML, Dizdaroglu M, Gajewski E, Essigmann JM. Mechanistic studies of ionizing irradiation and oxidative mutagenesis: genetic effects of a single 8-hydroxyguanine (7-hydro-8-oxoguanine) residue inserted at a unique site in a viral genome.Biochemistry. 1990;29:7024–7032.

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    Umemura T, Sai K, Takagi A, Hasegawa R, Kurokawa Y. Formation of 8-hydroxydeoxyguanosine (8-OH-dG) in rat kidney DNA after intraperitoneal administration of ferric nitrilotriacetate (Fe-NTA).Carcinogenesis. 1990;11:345–347.

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Zhang D, Okada S, Yu Y, Zheng P, Yamaguchi R, Kasai H. Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron-mediated peroxidation in Wistar rat kidney.Cancer Res. 1997;57:2410–2414.

    PubMed  CAS  Google Scholar 

  85. 85.

    Yamada M, Awai M, Okigaki T. Rapidin vitro transformation system for liver epithelial cells by iron chelate, Fe-NTA.Cytotechnology. 1990;3:149–156.

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Carmichael PL, Hewer A, Osborne MR, Strain AJ, Phillips DH. Detection of bulky DNA lesions in the liver of patients with Wilson’s disease and primary haemochromatosis.Mutat Res. 1995;326:235–243.

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    Nair J, Carmichael PL, Fernando RC, Phillips DH, Strain AJ, Bartsch H. Lipid peroxidation-induced etheno-DNA adducts in the liver of patients with the genetic metal storage disorders Wilson’s disease and primary hemochromatosis.Cancer Epidemiol Biomarkers Prev. 1998;7:435–440.

    PubMed  CAS  Google Scholar 

  88. 88.

    Hussain SP, Raja K, Amstad PA, et al. Increased p53 mutation load in nontumorous human liver of Wilson disease and hemochromatosis: oxyradical overload diseases.Proc Natl Acad Sci U S A. 2000;97:12770–12775.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  89. 89.

    Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron-chelation therapy with deferiprone for thalassemia major.N Engl J Med. 1998;339:417–423.

    PubMed  Article  CAS  Google Scholar 

  90. 90.

    Addis A, Loebstein R, Koren G, Einarson TR. Meta-analytic review of the clinical effectiveness of oral deferiprone (L1).Eur J Clin Pharmacol. 1999;55:1–6.

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    Pippard MJ, Weatherall DJ. Oral iron chelation therapy for thalassaemia: an uncertain scene.Br J Haematol. 2000;111:2–5.

    PubMed  Article  CAS  Google Scholar 

  92. 92.

    Richardson DR. The controversial role of deferiprone in the treatment of thalassemia.J Lab Clin Med. 2001;137:324–329.

    PubMed  Article  CAS  Google Scholar 

  93. 93.

    Kontoghiorghes GJ, Agarwal MB, Tondury P, Marx JJ. Deferiprone or fatal iron toxic effects?Lancet. 2001;357:882–883.

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Kowdley KV, Kaplan MM. Iron-chelation therapy with oral deferiprone: toxicity or lack of efficacy?N Engl J Med. 1998;339:468–469.

    PubMed  Article  CAS  Google Scholar 

  95. 95.

    Wonke B, Wright C, Hoffbrand AV. Combined therapy with deferiprone and desferrioxamine.Br J Haematol. 1998;103:361–364.

    PubMed  Article  CAS  Google Scholar 

  96. 96.

    Kontoghiorghes GJ, Pattichi K, Hadjigavriel M, Kolnagou A. Transfusional iron overload and chelation therapy with deferoxamine and deferiprone (L1).Transfus Sci. 2000;23:211–223.

    PubMed  Article  CAS  Google Scholar 

  97. 97.

    Wu W-H, Meydani M, Meydani SN, Burklund PM, Blumberg JB, Munro HN. Effect of dietary iron overload on lipid peroxidation, prostaglandin synthesis and lymphocyte proliferation in young and old rats.J Nutr. 1990;120:280–289.

    PubMed  Article  CAS  Google Scholar 

  98. 98.

    Golberg L, Martin LE, Batchelor A. Biochemical changes in the tissues of animals injected with iron.3.lipid peroxidation.Biochem J. 1962;83:291–298.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  99. 99.

    Hultcrantz R, Ericsson JLE, Hirth T. Levels of malondialdehyde production in rat liver following loading and unloading of iron.Virchows Arch B Cell Pathol Incl Mol Pathol. 1984;45:139–146.

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    Fletcher LM, Roberts FD, Irving MG, Powell LW, Halliday JW. Effects of iron loading on free radical scavenging enzymes and lipid peroxidation in rat liver.Gastroenterology. 1989;97:1011–1018.

    PubMed  Article  CAS  Google Scholar 

  101. 101.

    Britton RS, O’Neill R, Bacon BR. Hepatic mitochondrial malondialdehyde metabolism in rats with chronic iron overload.Hepatology. 1990;11:93–97.

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    Houglum K, Filip M, Witztum JL, Chojkier M. Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload.J Clin Invest. 1990;86:1991–1998.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  103. 103.

    Younes M, Trepkau H-D, Siegers C-P. Enhancement by dietary iron of lipid peroxidation in mouse colon.Res Commun Chem Pathol Pharmacol. 1990;70:349–354.

    PubMed  CAS  Google Scholar 

  104. 104.

    Valerio LG Jr, Petersen DR. Characterization of hepatic iron overload following dietary administration of dicyclopentadienyl iron (Ferrocene) to mice: cellular, biochemical, and molecular aspects.Exp Mol Pathol. 2000;68:1–12.

    PubMed  Article  CAS  Google Scholar 

  105. 105.

    Parkkila S, Niemela O, Britton RS, et al. Vitamin E decreases hepatic levels of aldehyde-derived peroxidation products in rats with iron overload.Am J Physiol. 1996;270:G376-G384.

    PubMed  CAS  Google Scholar 

  106. 106.

    Ramm GA, Li SCY, Li L, et al. Chronic iron overload causes activation of rat lipocytesin vivo.Am J Physiol. 1995;268:G451-G458.

    PubMed  CAS  Google Scholar 

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Correspondence to Robert S. Britton or Katherine L. Leicester or Bruce R. Bacon.

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Britton, R.S., Leicester, K.L. & Bacon, B.R. Iron Toxicity and Chelation Therapy. Int J Hematol 76, 219–228 (2002). https://doi.org/10.1007/BF02982791

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Key words

  • Iron
  • Hemochromatosis
  • β-Thalassemia
  • Oxidative stress
  • Iron chelators