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Tissue Iron Overload and Mechanisms of Iron-Catalyzed Oxidative Injury

  • Edward J. Lesnefsky
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 366)

Abstract

Tissue iron overload causes cell damage and organ dysfunction. The mechanisms of iron uptake by tissues and the probable biochemical pathways of iron-derived tissue injury will be reviewed. The iron-overload states are the initial clinical setting where the contribution of iron-catalyzed oxidative injury to the pathogenesis of a clinical disease has been appreciated. When viewed from the perspective of oxidative injury, the iron-overload syndromes also provide a model of tissue injury that is applicable to other disease states, including inflammation, ischemia-reperfusion injury, and anthracycline-induced cardiac toxicity. The goal of this chapter will be to provide a brief clinical overview of the iron-overload states, review the mechanisms of tissue iron uptake in normal and pathologic situations, the likely cellular targets and reactions of iron-catalyzed oxidative injury, and the clinical therapy of the iron-overload syndromes. The potential role of iron-catalyzed oxidative injury in the myocardial damage resulting from ischemia and reperfusion, and from anthracycline administration will also be discussed.

Keywords

Iron Overload Intracellular Iron Tissue Iron Cytosolic Pool Cytosolic Iron 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    J.L. Goldstein, M.S. Brown. Genetics and cardiovascular disease, in: Heart Disease A Textbook of Cardiovascular Medicine. E. Braunwald, ed., W.B. Saunders Company Philadelphia, PA. (1988).Google Scholar
  2. 2.
    D.S. Rosenthal, E. Braunwald. Hematological-oncological disorders and heart disease, in: Heart Disease A Textbook of Cardiovascular Medicine. E. Braunwald, ed., W.B. Saunders Company Philadelphia, PA. (1988).Google Scholar
  3. 3.
    D.M. Koeller, J.A. Horowitz, J.L. Casey, R.D. Klausner, J.B. Harford, Translation and the stability of mRNAs encoding the transferrin receptor and c-fos, Proc Natl Acad Sci USA 88:7778–7782 (1991).PubMedCrossRefGoogle Scholar
  4. 4.
    R.D. Klausner, J.B. Harford, Cis-trans models for post-transcriptional gene regulation. Science 246:870–872 (1989).PubMedCrossRefGoogle Scholar
  5. 5.
    P.C. Adams, L.A. Chau, Hepatic ferritin uptake and hepatic iron, Hepatology 11:805–808 (1990).PubMedCrossRefGoogle Scholar
  6. 6.
    J.C. Sibille, M. Ciriolo, H. Kondo, R.R. Crichton, P. Aisen, Subcellular localization of ferritin and iron taken up by rat hepatocytes, Biochem J 262:685–688 (1989).PubMedGoogle Scholar
  7. 7.
    R.A. Floyd, Direct demonstration that ferrous ion complexes of di-and triphosphate nucleotides catalyze hydroxyl free radical formation from hydrogen peroxide. Arch Biochem Biophys 225;263–270 (1983).PubMedCrossRefGoogle Scholar
  8. 8.
    R.A. Floyd, C.A. Lewis, Hydroxyl free radical formation from hydrogen peroxide by ferrous iron-nucleotide complexes, Biochemistry 22:2645–2649 (1983).PubMedCrossRefGoogle Scholar
  9. 9.
    M. Grootveld, J.D. Bell, B. Halliwell, O.I. Aruoma, A. Bomford, P.J. Sadler, Non-transferrin-bound iron in plasma or serum from patients with idiopathic hemochromatosis. Characterization by high performance liquid chromatography and nuclear magnetic resonance spectroscopy, J Biol Chem, 264:4417–4422 (1989).PubMedGoogle Scholar
  10. 10.
    G. Link, A. Pinson, C. Hershko, Heart cells in culture: a model of myocardial iron overload and chelation, J Lab Clin Med, 106:147–153 (1985).PubMedGoogle Scholar
  11. 11.
    J. Kaplan, I. Jordan, A. Sturrock, Regulation of the transferrin-independent iron transport system in cultured cells, J Biol Chem, 266:2997–3004 (1991).PubMedGoogle Scholar
  12. 12.
    J.G. Parkes, R.A. Hussain, N.F. Olivieri, D.M. Templeton, Effects of iron loading on uptake, speciation, and chelation of iron in cultured myocardial cells, J Lab Clin Med 122:36–47 (1993).PubMedGoogle Scholar
  13. 13.
    A. Jacobs, Low molecular weight intracellular iron transport compounds. Blood 50:433–439 (1977).PubMedGoogle Scholar
  14. 14.
    P. Biemond, A.J.G. Swaak, C.M. Beindorff, J.F. Koster JF, Superoxidedependent and-independent mechanisms of iron mobilization from ferritin by xanthine oxidase, Biochem J, 239:169–173 (1986).PubMedGoogle Scholar
  15. 15.
    G. Healing, J. Gower, B. Fuller, C. Green, Intracellular iron redistribution, an important determinant of reperfusion damage to rabbit kidneys, Biochem Pharm 7:1239–1245 (1990).CrossRefGoogle Scholar
  16. 16.
    S. Holt, M. Gunderson, K. Joyce, N.R. Nayini, G.F. Eyster, A.M. Garitano, C Zonia, G.S. Krause, S.D. Aust, B.C. White, Myocardial tissue iron derealization and evidence for lipid peroxidation after two hours of ischemia, Ann Emerg Med 15:1155–1159 (1986).PubMedCrossRefGoogle Scholar
  17. 17.
    S. Harel, M.A. Salan, J. Kanner, Iron release from methyoclobin, methemoglobin and cytochrome c by a system generating hydrogen peroxide, Free Rad Res Comms 5:11–19 (1988).CrossRefGoogle Scholar
  18. 18.
    S. Harel, J. Kanner, The generation of ferryl or hydroxyl radicals during interaction of haemproteins with hydrogen peroxide, Free Rad Res Comms 5:21–33 (1988).CrossRefGoogle Scholar
  19. 19.
    J.K. Brieland, J.C. Fantone, Ferrous iron release from transferrin by hemin neutrophil-derived superoxide anion: effect of pH and iron saturation. Arch Biochem Biophys 284:78–83 (1991).PubMedCrossRefGoogle Scholar
  20. 20.
    J.K. Brieland, S.J. Clarke, S. Karminol, S.H. Phan, J.C. Fantone, Transferrin: a potential source of iron for oxygen free radical-mediated endothelial cell injury, Arch Biochem Biophys 294:265–270 (1992).PubMedCrossRefGoogle Scholar
  21. 21.
    B. Halliwell, J.M.C. Gutteridge, Oxygen toxicity, oxygen radicals, transition metals and disease, Biochem J 219:1–14 (1984).PubMedGoogle Scholar
  22. 22.
    B. Halliwell, J.M.C. Gutteridge, Oxygen free radical and iron in relation to biology and medicine: Some problems and concepts, Arch Biochem Biophys 246:501–514 (1986).PubMedCrossRefGoogle Scholar
  23. 23.
    E. Graf, J.R. Mahoney, R.G. Bryant, J.W. Eaton, Iron-catalyzed hydroxyl radical formation, J Biol Chem 259:3620–3624 (1984).PubMedGoogle Scholar
  24. 24.
    L.A. Loeb, E.A. James, A.M. Waltersdorph, S.J. Klebanoff, Mutagenesis by the autoxidation of iron with isolated DNA, Proc Natl Acad Sci USA 85:3918–3922 (1988).PubMedCrossRefGoogle Scholar
  25. 25.
    H.W. Gardner, Oxygen radical chemistry of polyunsaturated fatty acids, Free Rad Biol Med 7:65–86 (1989).PubMedCrossRefGoogle Scholar
  26. 26.
    E.R. Stadtman, Metal ion-catalyzed oxidation of proteins: Biochemical mechanism and biological consequences Free Rad. Biol. Med 9:315–325 (1990).PubMedCrossRefGoogle Scholar
  27. 27.
    F.Z. Meerson, V.E. Kagan, N.P. Kozlov, L.M. Belkina, Y.V. Arkhipenko, The role of lipid peroxidation in pathogenesis of ischemic damage and the antioxidant protection of heart, Basic Res Cardiol 77:465–485 (1982).PubMedCrossRefGoogle Scholar
  28. 28.
    E.J. Lesnefsky, K.G.D. Allen, F.P. Carrea, L.D. Horwitz, Iron-Catalyzed Lipid Peroxidation Occurs in the Intact Heart: Detection Using a New Lipid Peroxide Assay, J Mol Cell Cardiol 24:1031–1038 (1992).PubMedCrossRefGoogle Scholar
  29. 29.
    K.P. Burton, J.M. McCord, G. Ghai, Myocardial alteration due to free radical generation. Am J Physiol 246:H776–H783 (1984).PubMedGoogle Scholar
  30. 30.
    J.M. Braughler, L.A. Duncan, R.L. Chase, The involvement of iron in lipid peroxidation, J Biol Chem 261:10282–10289 (1986).PubMedGoogle Scholar
  31. 31.
    J.M. Gutteridge, The role of superoxide and hydroxyl radicals in phospholipid peroxidation catalyzed by iron salts, FEBS Lett 150:454–458 (1982).PubMedCrossRefGoogle Scholar
  32. 32.
    J.R. Bucher, M. Tien, S.D. Aust, The requirement for ferric in the initiation of lipid peroxidation by chelated ferrous iron, Biochem Biophys Res Comm 111:777–784 (1983).PubMedCrossRefGoogle Scholar
  33. 33.
    J.M.C. Gutteridge, Lipid peroxidation initiated by superoxide-dependent hydroxyl radicals using complexed iron and hydrogen peroxide. FEBS Lett 172:245–249 (1984).PubMedCrossRefGoogle Scholar
  34. 34.
    P.J. O’Brien, Intracellular mechanisms for the decomposition of a lipid peroxide. I. Decomposition of a lipid peroxide by metal ions, heme compounds, and nucleophiles, Can J Biochem 47:485–499 (1969).PubMedCrossRefGoogle Scholar
  35. 35.
    B.A. Svinson, J.A. Buege, F.O. O’Neal, S.D. Aust, The mechanism of NADPH-dependent lipid peroxidation, J Biol Chem 254:5892–5899 (1979).Google Scholar
  36. 36.
    J.M. Gutteridge, R. Richmond, B. Halliwell, Inhibition of the iron-catalyzed formation of hydroxyl radicals from superoxide and of lipid peroxidation by desferrioxamine, Biochem J 184:469–472 (1979).PubMedGoogle Scholar
  37. 37.
    G. Cohen, P.M. Sinet, The Fenton reaction between ferrous-diethylene triamepenta-acetic acid and hydrogen peroxide. FEBS Lett 138:258–260 (1982).CrossRefGoogle Scholar
  38. 38.
    B.R. Bacon, R. O’Neill, Park C.H., Iron-induced peroxidative injury to isolated rat hepatic mitochondria. Free Rad Biol Med 2:339–347 (1986).CrossRefGoogle Scholar
  39. 39.
    B.R. Bacon, C.H. Park, G.M. Brittenham, R. O’Neil, A.S. Tavill, Hepatic mitochondrial oxidative metabolism in rats with chronic dietary iron overload, Hepatology 5:789–797 (1985).PubMedCrossRefGoogle Scholar
  40. 40.
    A. Masini, D. Ceccareli, T. Trenti, F.P. Corongiu, U. Muscatello, Perturbation in liver mitochondrial Ca2+homeostasis in experimental iron overload: a possible factor in cell injury, Biochim Biophys Acta 1014:133–140 (1989).PubMedCrossRefGoogle Scholar
  41. 41.
    G. Link, A. Pinson, Hershko C., Iron loading of cultured cardiac myocytes modifies sarcolemmal structure and increases lysosomal fragility. J Lab Clin Med 121:127–134 (1993).PubMedGoogle Scholar
  42. 42.
    I.T. Mak, W.B. Weglicki, Characterization of iron-mediated peroxidative injury in isolated hepatic lysosomes, I Clin Invest 75:58–63 (1985).CrossRefGoogle Scholar
  43. 43.
    K. Houglum, M. Filip, J.L. Witzutum, M. Choikier, Malondialdehyde and 4-hydroxynonenal protein adducts in plasma and liver of rats with iron overload, J Clin Invest 86:1991–1998 (1990).PubMedCrossRefGoogle Scholar
  44. 44.
    C.A. Seymour, T.J. Peters, Organelle pathology in primary and secondary haemochromatosis with special reference to lysosomal changes, Br I Haematol 40:239–253 (1978).CrossRefGoogle Scholar
  45. 45.
    M.P. Weir, J.F. Gibson, T.J. Peters, Haemodiserin and tissue damage, Cell Biochem Fund 2:186–194 (1984).CrossRefGoogle Scholar
  46. 46.
    A.D. Heys, T.L. Dormandy, Lipid peroxidation in iron loaded spleens, Clin Sci 60:295–301 (1981).PubMedGoogle Scholar
  47. 47.
    L. Wolfe, N. Olivieri, D. Sallan, Prevention of cardiac disease by subcutaneous deferoxamine in patients with thalassemia major, New Engl J Med 312:1600–1603 (1985).PubMedCrossRefGoogle Scholar
  48. 48.
    A. Cohen, Current status of iron chelation therapy with deferoxamine, Semin Hematol 27:86–90 (1990).PubMedGoogle Scholar
  49. 49.
    R. Marcus, S. Davies, H. Bantock, S. Underwood, S. Walton, E. Huehns, Desferrioxamine to improve cardiac function in iron-overloaded patients with thalassemia major, Lancet 1:392–393 (1984).PubMedCrossRefGoogle Scholar
  50. 50.
    S. Hoe, D.A. Rowley, B. Halliwell, Reactions of ferrioxamine and desferrioxamine with the hydroxyl radical, Chem Biol Inter 41:75–81 (1982).CrossRefGoogle Scholar
  51. 51.
    E.J. Lesnefsky, J.E. Repine, L.D. Horwitz, Deferoxamine pretreatment reduces canine infarct size and oxidative injury, J Pharm Exp Ther 253:1103–1109 (1990).Google Scholar
  52. 52.
    R. Laub, Y.J. Schneider, J.N. Octave, A. Trouet, R.R. Crichton, Cellular pharmacology of deferoxamine B and derivatives in cultured rat hepatocytes in relation to iron mobilization, Biochem Pharm 34:1175–1183 (1985).PubMedCrossRefGoogle Scholar
  53. 53.
    D.E. Gannon, J. Varani, S.H. Phan, J.H. Ward, J. Kaplan, G.O. Till, R.H. Simon, U.S. Ryan, P.A. Ward, Source of iron in neutrophil-mediated killing of endothelial cells, Lab Invest 57:37–44 (1987).PubMedGoogle Scholar
  54. 54.
    G.J. Kontoghiorghes, The study of iron mobilisation from transferrin using aketohydroxy heteroaromatic chelators, Biochim Biophys Acta 869:141–146 (1986).PubMedCrossRefGoogle Scholar
  55. 55.
    J.B. Porter, M. Gyparaki, L.C. Burke, E.R. Huehns, P. Sarpong, V. Saez, R.C. Hider, Iron mobilization from hepatocyte monolayer cultures by chelators: the importance of membrane permeability and the ironbinding constant, Blood 72:1497–1503 (1988).PubMedGoogle Scholar
  56. 56.
    P. Tondury, G.J. Kontoghiorghes, A. Ridolfi-Luthy, A. Hirt, A.V. Hoffbrand, AM. Lottenbach, T. Sonderegger, H.P. Wagner, L1 (l,2-dimethyl-3-hydroxypyrid-4-one) for oral iron chelation in patients with betsthalassemia major, Br J Haematol 76:550–553 (1990).PubMedCrossRefGoogle Scholar
  57. 57.
    N.R. Olivieri, G. Koren, C. Hermann, Y. Bentur, D. Chung, J. Lkein, P. St. Louis, M.H. Freedman, R.A. McClelland, D.M. Templeton, Comparison of oral iron chelator L1 and desferrioxamine in iron-loaded patients, Lancet 336:1275–1279 (1990).PubMedCrossRefGoogle Scholar
  58. 58.
    G.J. Kontoghorgies, A. Piga, A.V. Hoffbrand, Cytotoxic and DNA-inhibitory effects of iron chelators on human leukaemic cell lines. Hematol Oncol 4:195–204 (1986).CrossRefGoogle Scholar
  59. 59.
    J.L. Sullivan, The iron paradigm of ischemic heart disease, Am Heart J 117:1177–1188 (1989).PubMedCrossRefGoogle Scholar
  60. 60.
    J.T. Salonen, K. Nyyssonen, H. Koppela, J. Tuomilehto, R. Seppanen, R. Salonen, High stored iron levels are associated with excess risk of myocardial infarction in Finnish men. Circulation 86:803–811 (1992).PubMedCrossRefGoogle Scholar
  61. 61.
    R.E. Williams, J.L. Zweier, J.T. Flaherty, Treatment with deferoxamine during ischemia improves functional and metabolic recovery and reduces reperfusion-induced oxygen radical generation in rabbit hearts, Circulation 83:1006–1014 (1991).PubMedCrossRefGoogle Scholar
  62. 62.
    A.M.M. van der Kraaij, H.G. van Eijk, J.F. Koster, Prevention of postischemic cardiac injury by the orally active iron chelator 1,2-dimethyl-3-hydroxy-4-pyridone (L1) and the antioxidant ( + )-cyanidanol-3, Circulation 80:158–164 (1989).PubMedCrossRefGoogle Scholar
  63. 63.
    B.R. Reddy, R.A. Kloner, K. Przyklenk, Early treatment with deferoxamine limits myocardial ischemic/reperfusion injury, Free Rad Biol Med 7:45–52 (1989).PubMedCrossRefGoogle Scholar
  64. 64.
    E.J. Lesnefsky, J. Ye, Exogenous Intracellular, But Not Extracellular, Iron Augments Myocardial Oxidative Injury During Ischemia and Reperfusion, Am J Physiol (1994).Google Scholar
  65. 65.
    E.J. Lesnefsky, J. Ye, Excess Intracellular, But Not Extracellular Iron Augments Myocardial Lipid Peroxidation and Injury During Reperfusion. Clin Res 39:691A (1991).Google Scholar
  66. 66.
    R. Engler, E. Gilpin, Can superoxide dismutase alter myocardial infarct size? Circulation 79:1137–1142 (1989).PubMedCrossRefGoogle Scholar
  67. 67.
    F.P. Carrea, E.J. Lesnefsky, J.E. Repine, R.H. Shikes, L.D. Horwitz, Reduction of Canine Myocardial Infarct Size by a Diffusible Reactive Oxygen Metabolite Scavenger: Efficacy of Dimethylthiourea Given at the Onset of Reperfusion, Circ Res 68:1652–1659 (1991).PubMedCrossRefGoogle Scholar
  68. 68.
    S.E. Mitsos, T.E. Askew, J.C. Fantone, S.L. Kunkel, G.D. Abrams, A. Schork, B.R. Lucchesi, Protective effects of N-2-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: evidence for the role of intracellular-derived free radicals, Circulation 73:1077–1086 (1986).PubMedCrossRefGoogle Scholar
  69. 69.
    E.J. Lesnefsky, Reduction of Infarct Size by Cell Permeable Oxygen Metabolite Scavengers. Free Rad Biol and Med 12:429–446 (1992).CrossRefGoogle Scholar
  70. 70.
    R.C. Young, R.F. Ozols, C.E. Myers, The anthracycline antineoplastic drugs. N Engl J Med 305:139–153 (1981).PubMedCrossRefGoogle Scholar
  71. 71.
    C.E. Myers, W.P. McGuire, R.H. Liss, Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 197:165–167 (1977).PubMedCrossRefGoogle Scholar
  72. 72.
    P.K. Singal, G.N. Pierce, Adriamycin stimulates low affinity Ca2+ binding and lipid peroxidation but depresses myocardial function. Am J Physiol 250:H419–H425 (1986).PubMedGoogle Scholar
  73. 73.
    C. Hershko, G. Link, M. Tzahor, J.P. Kaltwasser, P. Athias, A. Grynberg, A. Pinson. Anthracycline toxicity is potentiated by iron and inhibited deferoxamine: Studies in rat heart cells in culture. J Lab Clin Med 122:245–251 (1993).PubMedGoogle Scholar
  74. 74.
    J.L. Speyer, M.D. Green, A. Zeleneiuch-Jacquotte, J.C. Wernz, M. Rey, J. Sanger, E. Kramer, V. Ferrans, H. Hochster, M. Meyers, et al, ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol 10:117–127 (1992).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1994

Authors and Affiliations

  • Edward J. Lesnefsky
    • 1
  1. 1.Division of Cardiology, Cleveland VA Medical CenterCase Western Reserve UniversityClevelandUSA

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