Oxygen Toxicity: Role of Hydrogen Peroxide and Iron

  • B. S. van Asbeck
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 264)


An important factor in tissue damage by toxic oxygen species is the ability to increase the level of hydrogen peroxide. This inter mediate of oxygen reduction is not only a precursor of species with a higher reactivity, such as the hydroxyl radical, but it also controls the process of inflammatation by its effect on the synthesis of vasoactive and chemotactic compounds. However, tissue injury by hydrogen peroxide often, if not always, depends on the availability of catalytic iron.


Oxygen Toxicity Arachidonic Acid Metabolism Ferric Citrate Human Polymorphonuclear Leukocyte Ferroxidase Activity 
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  1. 1.
    Freeman, B.A., Crapo, J.D.: Biology of disease. Free radicals and tissue injury. Lab Invest 47: 412–426, 1982.Google Scholar
  2. 2.
    Cross, C.E. : Oxygen radicals and human disease. Ann of Intern Med 107: 524–545, 1987.Google Scholar
  3. 3.
    Babior, B.M.: Oxygen-dependent microbial killing by phagocytes (two parts). N Engl J Med. 298: 659-668; 721–725, 1978.Google Scholar
  4. 4.
    Beauchamp, C., Fridovich, I.: A mechanism for the production of sthylene from methional. The generation of the hydroxyl radical by xanthine oxidase. J Biol Chem 245: 4641–4646, 1970.Google Scholar
  5. 5.
    Henricks, P.A.J., Van der Tol, M.E., Thyssen R.M.W., Van Asbeck, B.S., Verhoef J.: Escherichia coli lipopolisaccharides diminish and enhance cell function of human polymorphonuclear leukocytes. Infect Immun 41: 294–301, 1983.PubMedGoogle Scholar
  6. 6.
    Wrigglesworth, J.M., Baum, H.: The biochemical functions of iron. In: Iron in Biochemistry and Medicine. II. Jacobs A, Worwood M eds, Academic Press, London and New York, pp. 29–86, 1980.Google Scholar
  7. 7.
    Starke, P.E., Farber, J.L.: Ferric iron and Superoxide 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 260: 10099–10104, 1985.Google Scholar
  8. 8.
    Roots, R., Okada, S: Estimation of life times and diffusion distances of radicals involved in X-ray-induced DNA strand breaks or killing of mammalian cell. Radiat Res 64: 306–320, 1975.PubMedCrossRefGoogle Scholar
  9. 9.
    Weiss, S.J.: Mechanisms of disease; tissue destruction by neutrophils. N Engl J Med 320: 365–376, 1989.PubMedCrossRefGoogle Scholar
  10. 10.
    Egan, R.W., Gale, P.H. Kuehl, F.A. Jr.: Reduction of hydroperoxides in the prostaglandin biosynthetic pathway by a microsomal peroxidase. J Biol Chem 254: 3295–3302, 1979.PubMedGoogle Scholar
  11. 11.
    Rosenblum, W.I.: Hydroxyl radical mediates the endotheliumdependent relaxation produced by bradykinin in mouse cerebral arterioles. Circ Res. 61: 601–603, 1987.PubMedGoogle Scholar
  12. 12.
    Lewis, S.L., Whatley, R.E., Cainf P., Mclntyre, T.M., Prescott, S.M., Zimmerman, G.A.: Hydrogen peroxide stimulates the synthesis of platelet-activating factor by endothelium and induces endothelial cell-dependent neutrophil adhesion. J Clin Invest. 82: 2045–2055, 1988.PubMedCrossRefGoogle Scholar
  13. 13.
    Rush, D.N., McKenna, R.M., Walker, S.M., Bakkestad-Legare, P., Jeffrey, J.R.: Catalase increases lymphocyte proliferation in mixed lymphocyte culture. Transpl Proceed 20: 1271–1273, 1988.Google Scholar
  14. 14.
    Larsson, R., Cerutti, P.: Oxidants induce phosphorylation of ribosomal protein S6. J Biol chem 263, 17452–17458, 1988.PubMedGoogle Scholar
  15. 15.
    Arrick, B.A., Nathan, C.F., Griffith, O.W., Cohn, Z.A.: Glutathione depletion sensitizes tumor cells to oxidative cytolysis. J Biol Chem 257: 1231–1237, 1982.PubMedGoogle Scholar
  16. 16.
    Arrick, B.A., Nathan, C.F., Cohn, Z.A.: Inhibition of glutathione synthesis augments lysis of murine tumor cells by sulfhydrylreactive antineoplastics. J Clin Invest 71: 258–267, 1983.PubMedCrossRefGoogle Scholar
  17. 17.
    Mitchell, J.B., Russo, A.: Role of glutathione in radiation and drug induced cytotoxicity. Proceedings of the 13th L.H. Gray Con ference, Brunei University, West London, 14–18 July, 1986. pp. 96.Google Scholar
  18. 18.
    Bernard, G.R., Lucht, W.D., Niedermeyer, M.E., Snapper, J.R., Ogletree, M.L., Brigham, K.L.: Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest 73:1772–1784, 1984.PubMedCrossRefGoogle Scholar
  19. 19.
    Van Asbeck, B.S., Van der Wal, W.A.A., Heesbeen, E.C., Brandt, C.J.W.M., Vosmeer, J.W.G., Van Oirschot, J.F.L.M.: Crucial role for lung glutathione in protection against hyperoxia. Amer Rev Resp Dis 135: All 1987Google Scholar
  20. 20.
    Wagner, P.D., Mathieu-Costello, O., Bebout, D.E., Gray, A.T., Natterson, P.D., Glennow, G.: Protection against pulmonary O2 toxicity by N-acetylcysteine. Eur Respir J 2: 116–126, 1989.PubMedGoogle Scholar
  21. 21.
    Williamson, J.M., Boettcher, B., Meister, A.: Intracellular cysteine delivery system that protects against toxicity by promoting glutathione synthesis. Proc Natl Acad Sci 79: 6246–6249, 1982.PubMedCrossRefGoogle Scholar
  22. 22.
    Moldéus, P., Cotgreave, I.S., Berggren, M. : Lung protection by a thiol-containing antioxidant: N-acetylcysteine. Respiration 50, supp 1:31–42, 1986.Google Scholar
  23. 23.
    Nakayama, T., Kaneko, M., Kodama, M., Nagat, C.: Cigarette smoke induces DNA single-strand breaks in human cells. Nature 314: 462–464, 1985.PubMedCrossRefGoogle Scholar
  24. 24.
    Meister, A.: Selective modification of glutathione metabolism. Science 220: 473–477, 1983.CrossRefGoogle Scholar
  25. 25.
    Aisen P: Some physiochemical aspects of iron metabolism. In: Iron metabolism. Ciba Foundation Symposium. Elsevier: Exerpta Medica/ North-Holland Inc, Amsterdam pp. 1–17, 1977.Google Scholar
  26. 26.
    Haber, F., Weiss, J: The catalytic decompensation of hydrogen peroxide by iron salts. Proc Roy Soc Lond (A) 147: 332–351, 1934.CrossRefGoogle Scholar
  27. 27.
    Fenton HJH: Oxidation of tartaric acid in presence of iron. J Chem Soc 65: 899–910, 1894.CrossRefGoogle Scholar
  28. 28.
    Sadrzadeh, S., Graf, E., Panter, S.S., Hallaway, P.E.,Eaton, J.W.: Hemoglobin. A biologic fenton reagent. J Biol Chem 259:14354–14356, 1984.Google Scholar
  29. 29.
    Sausville, E.A., Peisach, J., Horwitz, S.B.: Effect of chelating agents and metal ions on the degradation of DNA by bleomycin. Chemistry 17: 2740–2746, 1978.Google Scholar
  30. 30.
    Smith, L.L., Rose, M.S., Wyatt, I.: The pathology and biochemistry of paraquat. London: Symposium on Oxygen Free Radicals and Tissue Damage: 321–431, 1976.Google Scholar
  31. 31.
    Bus, J.S., Gibson, J.E., Paraquat: model for oxidant-initiated toxicity. Environ Health Perspect 55: 37–46, 1984.PubMedCrossRefGoogle Scholar
  32. 32.
    McCord, J.M., Day, E.D. Jr.: Superoxide-dependent production of hydroxyl radical catalyzed by iron-EDTA complex. FEBS Lett 86: 139–142, 1978.PubMedCrossRefGoogle Scholar
  33. 33.
    Land, E.J., Swallow, A.J.: Electron transfer from pyridinyl radicals to cytochrome c. Berl Bunsenges Phys Chem 79: 436–437, 1975.Google Scholar
  34. 34.
    Patterson, L.K., Small, R.D. Jr, Scaiano, L.C.: Reaction of paraquat radical cations with oxygen: a pulse radiolysis and laser photolysis study. Radiat Res 72: 218–225, 1977.CrossRefGoogle Scholar
  35. 35.
    Martell, A.E.: The design and synthesis of chelating agents. In: development of iron chelators for clinical use. Martell AE, Anderson WF, Badman DG, Elsevier/North-Holland, New York, Amsterdam, Oxford, pp. 67–131, 1981.Google Scholar
  36. 36.
    Dwyer, F.P.: Enzym-metal ion activation and catalytic phenomena with metal complexes. Chelating Agents and Metal Chelates. Dwyer F.P., Melloor D.P.,. Academic Press, New York, London, pp. 335–382, 1964.Google Scholar
  37. 37.
    Graf, E., Mahoney, J.R., Bryant, R.G., Eaton, J.W.: Iron-catalyzed hydroxyl radical formation. J Biol Chem 259: 3620–3624, 1984.PubMedGoogle Scholar
  38. 38.
    Martell, A.E., Gustafson, R., Chaverek, S.: Metal chelate com pounds in homogenous aqueous catalysis. Advances in Catalysis IX. Farkas A ed. Academic Press, New York, pp. 319–322, 1957.Google Scholar
  39. 39.
    Schwarzenbach, G., Heller, J.: Die Eisenkomplexe der Nitrolotriessigsäure. Helv Clin Acta 34: 1889–1901, 1951.CrossRefGoogle Scholar
  40. 40.
    Spiro, T.G., Pape, L., Saltman, P.: The hydrolytic polymerization of ferric citrate. I. Chemistry of the polymer. J Am Chem Soc 89: 5555–5558, 1967.CrossRefGoogle Scholar
  41. 41.
    Spiro, T.G., Bates, G., Saltman, P.: The hydrolytic polymerization of ferric citrate. II. The influence of excess citrate. J Am Chem Soc 89: 5559–5562, 1967.Google Scholar
  42. 42.
    Van Asbeck, B.S., Marx, J.J.M., Struyvenberg, A., Van Kats, J.H., Verhoef, J. : Effect of iron (III) in the presence of various ligands on the phagocytic and metabolic activity of human polymorphonuclear leukocytes. J of Immunol 132: 851–856,1984.Google Scholar
  43. 43.
    Lind, M.D., Hamor, M.J., Hoard, J.L.: Sterochemistry of ethylenediamine-tetraacetato complexes. Inorg Chem 3: 34–43, 1984.CrossRefGoogle Scholar
  44. 44.
    Keberle, H. : The biochemistry of desferrioxamine and its relation to iron metabolism. Ann NY Acad Sci 119: 758–768, 1964.PubMedCrossRefGoogle Scholar
  45. 45.
    Aisen, P.: Iron transport and storage proteins. Ann Rev Biochem 49: 357–393, 1980.PubMedCrossRefGoogle Scholar
  46. 46.
    Bates, G.W., Workman, E.F. Jr., Schlabach, M.R.: Does transferrin exhibit ferroxidase activity. Biochem Bioph Res Com 50: 84–90, 1973.CrossRefGoogle Scholar
  47. 47.
    Gutteridge, J.M.C., Richmond, R., Halliwell, B.: Inhibition of the iron-catalyzed fromation of hydroxyl radicals from Superoxide and of lipid peroxidation by desferrioxamine. Biochem J 184: 469–472, 1979.PubMedGoogle Scholar
  48. 48.
    White, J.R., Yeowell, H.N.: Iron enhances the bacterial action of streptonigrin. Biochem Biophys Res Commun 106: 407–411, 1982.PubMedCrossRefGoogle Scholar
  49. 49.
    Kohen, R., Chevion, M.: Paraquat toxicity is enhanced by iron and reduced by desferrioxamine in laboratory mice. Biochem Pharmacol 34: 1841–1843, 1985.PubMedCrossRefGoogle Scholar
  50. 50.
    Van Asbeck, B.S., Hillen, F.C., Boonen, H.C.M., De Jong, Y., Dormans, J.A.M.A., Van der Wal, N.A.A., Marx, J.J.M., Sangster, B.: Continuous Intravenous Infusion of deferoxamine reduces mortality by paraquat in vitamin E-deficient rats. Am Rev Respir Dis 139: 769–773, 1989.PubMedGoogle Scholar
  51. 51.
    Bolli, R., Patel, B.S., Zhu, W., O’Neill, P.G., Hartley, C.J., Charlat, M.L., Roberts, R. : The iron chelator desferrioxamine attenuates postischemic ventricular dysfunction. Am Physiolog Soc: 1372–1380, 1987.Google Scholar
  52. 52.
    Farber, N.E., Vercellotti, G.M., Jacob, H.S., Pieper, G.M., Gross, G.J.: Evidence for a role of iron-catalyzed oxidants in function al and metabolic stunning in the canine heart. Circ Res 63: 351–360, 1988.PubMedGoogle Scholar
  53. 53.
    Van der Kraaij AMM, Mostert LJ, Van Eijk HG, Koster JF: Ironload increases the susceptibility of rat hearts to oxygen reperfusion damage. Circulation 78: 442–449, 1988.PubMedCrossRefGoogle Scholar
  54. 54.
    Grisaru, D., Goldfarb, A.W., Gotsman, M.S., Rachmilewitz, E.A., Hasin, Y. : Deferoxamine improves left ventricular function in thalassemia. Arch Intern Med 146: 2344–2349, 1986.PubMedCrossRefGoogle Scholar
  55. 55.
    Menasché, P., Pasquier, C., Bellucci, S., Lorente, P., JailIon, P., Piwnica, A.: Deferoxamine reduces neutrophil-mediated free radical production during cardiopulmonary bypass in mann. J Thorac Cardiovasc Surg 96: 582–587, 1988.PubMedGoogle Scholar
  56. 56.
    Van Asbeck, B.S., Marx, J.J.M., Struyvenberg, A, Van Kats, J.H., Verhoef, J.: Deferoxamine enhances phagocytic function of human polymorphonuclear leukocytes. Blood 63: 714–720, 1984.PubMedGoogle Scholar
  57. 57.
    Andrews, F.J., Morris, C.J., Kondratowicz, G., Blake, D.R.: Effect of iron chelation on inflammatory joint disease. Ann of Rheum Dis 46: 327–333, 1987.CrossRefGoogle Scholar
  58. 58.
    Vercellotti, G.M., Van Asbeck, B.S., Jacob, H.S.: Oxygen radical induced erythrocyte hemolysis by neutrophils: critical role of iron and lactoferrin. J Clin Invest 76: 956–962, 1985.PubMedCrossRefGoogle Scholar
  59. 59.
    Ward, P.A., Till, G.O., Kunkel, R., Beauchamp, C. : Evidence for role of hydroxyl radical in complement and neutrophil-dependent tissue injury. J. Clin. Invest. 72: 789–801, 1983.PubMedCrossRefGoogle Scholar
  60. 60.
    Gannon, D.E., J. Varani, Phan, S.H., Ward, J.H., Kaplan, J., Till, G.O., Simon, R.H., Ryan, U.S., Ward, P.A.: Source of iron in neutrophil-mediated killing of endothelial cells. Lab Invest 57: 37–44, 1987.PubMedGoogle Scholar
  61. 61.
    Fuller, B.J., Lunec, J., Healing, G., Simpkin, S., Green, C.J.: Reduction of susceptibility to lipid peroxidation by desferriox amine in rabbit kidneys subjected to 24-hour cold ischemia and reperfusion. Transplantation 43: 604–606, 1986.Google Scholar
  62. 62.
    Menasché, P., Grousset, M.D.C., Gauduel, Y., Mouas, C., Pitwnica, A. : Prevention of hydroxyl radical formation: a critical concept for improving cardioplegia.Circulation 76 suppl. V: 180–185, 1987.Google Scholar
  63. 63.
    Cerchiari, E.L., Hoel, T.M., Safar, P., Sclabassi, S.J.: Protective effects of combined Superoxide dismutase and deferoxamine on recovery of cerebral blood flow and function after cardiac arrest in dogs. Stroke 18: 869–878, 1987.PubMedCrossRefGoogle Scholar
  64. 64.
    Hershko, C., Rachmilewitz, E.A.: The inhibitory effect of vitamin E on desferrioxamine-induced iron excretion in rats. Proc Soc Exp Biol Med 152: 249–252, 1976.PubMedGoogle Scholar
  65. 65.
    Slade, R., Stead, A.G., Graham, J.A., Hatch, G.E.: Comparison of lung antioxidant levels in humans and laboratory animals. Am Rev Respir Dis 131: 742–746, 1985.PubMedGoogle Scholar
  66. 66.
    Halliwell, B.: Evidence for a direct reaction between desferal and the Superoxide radical. Biochem Pharm 34: 229–233, 1985.PubMedCrossRefGoogle Scholar
  67. 67.
    Davies, M.J., Donkor, R., Dunster, CA., Gee, C.A., Jonas, S., Willson, R.L.: Desferriozamine (desferal) and Superoxide free radicals. Biochem J 246: 725–729, 1987.PubMedGoogle Scholar
  68. 68.
    Harris D.C., Aisen, P.: Facilitation of Fe(II) autoxidation by Fe(III) complexing agents. Biochim Biophys Acta 329: 156, 1973.Google Scholar
  69. 69.
    Goodwin, J.F., Whitten, C.F.: Chelation of ferrous sulphate solutions by desferrioxamine B. Nature 205: 281, 1965.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • B. S. van Asbeck
    • 1
  1. 1.Department of MedicineUniversity of UtrechtUtrechtThe Netherlands

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