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Protective Effects of Superoxide Dismutase Related to Its Preferential Binding to Monocytes

  • Ingrid Emerit
  • Jany Vassy
  • Frédéric Garban
  • Paulo Filipe
  • Joao Freitas
Chapter
Part of the NATO ASI Series book series (NSSA, volume 296)

Abstract

Superoxide dismutase (SOD) was used as a drug under the trade name Palosein before the enzymatic nature of this metallo-protein and the importance of superoxide release by inflammatory cells were recognized. The beneficial effects observed in joint disease of horses may have determined the choice of rheumatid arthritis and osteoarthritis as the first human diseases to be treated with this antioxidant enzyme. The first pilot study with bovine Cu—Zn SOD was published by Lund-Olesen and Menander (1974), and the promising results were confirmed in the following by several placebo-controlled double-blind clinical trials in patients with osteoarthritis (Flohé, 1988). However, improvement was not observed for all clinical and laboratory parameters chosen for the study. Intraarticular injection appeared to be more efficient than systemic treatment. Many other diseases were treated with SOD, including ischemia-reperfusion injury, organ transplantation, side effects of radiation and chemotherapy. For a large number of pathologies, however, the reports remained anecdotical. The general acceptance of SOD as a drug was retarded for various reasons, among which the results of pharmacodynamic studies were probably the most important. Because of the rapid clearance of the enzyme through the kidney, the clinical observations of therapeutic effects were doubted. Efforts were made to increase its maintainance in the circulation by binding the enzyme to various macromolecules, in particular polyethylene glycol. There was also considerable discussion with respect to the dosage. The first clinical trials in rheumatic disease were based on the doses found to beefficient in animal models of inflammation and varied between 2-16 mg daily. These models of inflammation had shown a bell-shaped dose response curve, higher doses being less effective than lower doses (Baret et al., 1984; Michelson et al., 1986; Vaille et al., 1990). Similar observations were reported later for SOD application after reperfusion of ischemic organs, where very high doses had been applied by bolus injection (Omar and McCord, 1990). The concept that SOD acts therapeutically according to its documented catalytic function on superoxide anion radicals released into the extracellular space was also doubtful, since there was no correlation between antiinflammatory activity and the level of circulating exogenous SOD (Baret et al., 1984). It was suggested that the anti-inflammatory action of exogenous SOD is due to attachment of the enzyme to the cell membrane (Michelson et al., 1986). This notion was supported by observations from our laboratory, demonstrating prevention of perinuclear halo formation in UVA-exposed fibroblast cultures by pretreatment with exogenous SOD, even after rinsing of the cells and resuspension in fresh, SOD-free medium before irradiation (Emerit et al., 1981). Recent observations of anticlastogenic effects in SOD-pretreated and washed lymphocyte cultures yielded similar results, which stimulated the investigations reported here.

Keywords

Superoxide Production Confocal Laser Microscopy FITC Fluorescence Clastogenic Effect Release Tumor Necrosis Factor 
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. Baret, A., Jadot, G., Puget, K., 1984, Pharmacocinetic and antiinflammatory properties in the rat of superoxide dismutases from various species. Biochem. Pharmacol. 33: 2755–2760.CrossRefGoogle Scholar
  2. Beckman, J.S., Minor, R.L., White, C.W., Repine, J.E., Rosen, G.M., Freeman, B.A., 1988, Superoxide dismutase and catalase conjugated to polyethylene glycol increases endothelial enzyme activity and oxidant resistance. J. Biol. Chem. 263: 6884–6892.Google Scholar
  3. Blakeley, W.F., Fuciarelli, A.F., Wegher, B.J., Dizdaroglu, M., 1990, Hydrogen peroxide induced base damage in deoxyribonucleic acid. Radiation Res. 121: 338–343.CrossRefGoogle Scholar
  4. Dini, L., and Rotilio, G., 1989, Electron microscopic evidence for endocytosis of superoxide dismutase by hepatocytes using protein-gold adducts. Biochem. Biophys. Res. Commun. 162: 940–944.CrossRefGoogle Scholar
  5. Emerit, I., 1994, Reactive oxygen species, chromosome mutation and cancer: Possible role of clastogenic factors in carcinogenesis. Free Radic. Biol. Med. 16: 99–109.CrossRefGoogle Scholar
  6. Emerit, I., Michelson, A.M., Martin, E., Emerit, J., 1981, Perinuclear halo formation as an indication of phototoxic effects. Dermatologica 163: 295–299.CrossRefGoogle Scholar
  7. Emerit, I. Garban, F., Vassy, J., Levy, A., Filipe, P., Freitas, J., 1996, Superoxide-mediated clastogenesis and anti-clastogenic effects of exogenous superoxide dismutase. Proc. Natl. Acad. Sci. USA 93:12799–12804.Google Scholar
  8. Flohé, L., 1988, Superoxide dismutase for therapeutic use: Clinical experience, dead ends and hopes. Mol. Cellul. Biochem. 84: 123–131.CrossRefGoogle Scholar
  9. Kyle, M.E., Nakae, D., Sakaida, I., Miccadei, S., Farber, J.L., 1988, Endocytosis of superoxide dismutase is required in order for the enzyme to protect hepatocytes from the cytotoxicity of hydrogen peroxide. J. Biol. Chem. 263: 3784–3789.Google Scholar
  10. Lund-Olesen, K., Menander K.B., 1974, Orgoteine, a new antiinflammatory metalloprotein drug: Preliminary evaluation of clinical efficacy and safety in degenerative joint disease. Curr. Ther. Res. 16: 706–717.Google Scholar
  11. Mello-Filho, A.C., Meneghini, R., 1984, In vivo formation of single strand breaks in DNA is mediated by the Haber Weiss reaction. Biochem. Biophys. Acta 781: 56–63.CrossRefGoogle Scholar
  12. Michelson, A.M., Puget, K., 1980, Cell penetration by exogenous superoxide dismutase. Acta Physiol. Scand. Suppl. 492: 67–80.Google Scholar
  13. Michelson, A.M., Puget, K, Jadot, G., 1986, Anti-inflammatory activity of superoxide dismutases: Comparison of enzymes from different sources in different models in rats: Mechanism of action. Free Radic. Res. Commun. 2: 43–56.CrossRefGoogle Scholar
  14. Nordenson, I., 1977., Effect of superoxide dismutase and catalase on spontaneously occuring chromosome breaks in patients with Fanconi’s anemia. Hereditas 82: 147–149.Google Scholar
  15. Nordenson, I., Beckman, G., Beckman L., 1976, The effect of superoxide dismutase and catalase on radiation-induced chromosome breaks. Hereditas 82: 125–128.CrossRefGoogle Scholar
  16. Ochi, T., Cerutti, P., 1987, Clastogenic action of hydroperoxy, 5,8,11,13-icosatetraenoic acids in mouse embryo fibroblasts C3H/10 1/2. Proc. Natl. Acad. Sci. USA 84: 990–994.CrossRefGoogle Scholar
  17. Omar, B.A., McCord, J.M., 1990, The cardioprotective effect of Mn-Superoxide dismutase is lost at high doses in the postischemic isolated rabbit heart. Free Radic. Biol. Med. 9: 465–479.CrossRefGoogle Scholar
  18. Vaille, A., Jadot, G., Elizagaray, A., 1990, Anti-inflammatory activity of various superoxide dismutases on polyarthritis in the Lewis rat. Biochem. Pharmacol. 39: 247–255.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Ingrid Emerit
    • 1
  • Jany Vassy
    • 2
  • Frédéric Garban
    • 1
  • Paulo Filipe
    • 3
  • Joao Freitas
    • 3
  1. 1.Institut Biomédical des CordeliersUniversity of Paris VIFrance
  2. 2.Laboratoire d’Analyse d’Images en Pathologie Cellulaire Hôpital Saint LouisParisFrance
  3. 3.Department of Dermatology Hôpital Santa MariaUniversity of LisbonPortugal

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