Skip to main content
SpringerLink
Log in

Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation

  • Commentary
  • Published:
Agents and Actions Aims and scope Submit manuscript

Abstract

The anti-inflammatory role of copper is well-known although still largely unexplained. On the other hand, the capacity of copper to induce the formation of damaging ·OH radicalsin vivo is no longer debated. These two aspects of the physiological activity of copper have been considered to be paradoxical. Arguments developed here show that they may actually derive from a single chemical process, the type of physiological effect observed depending on the ligand bound to the copper ions involved in Fenton chemistry.

Both iron and copper are Fenton catalysts. Given its intrinsic coordination properties, however, copper induces more site-specific ·OH damage to the ligands bound to it. It, therefore, appears that copper complexes with specific·OH-inactivating ligands (OILs) can be used as “lures” for the Fenton reaction, ·OH radicals preferentially formed on these being immediately inactivated.

The hypothesis is thus put forward here thatcopper-OIL complexes acting as effective Fenton catalysts are potential “catalase-like” anti-inflammatory drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. J. R. J. Sorenson,Copper complexes offer a physiological approach to treatment of chronic diseases. Prog. Med. Chem.26, 437–568 (1989).

    PubMed  Google Scholar 

  2. O. I. Aruoma, B. Halliwell, E. Gajewski and M. Dizdaroglu,Copper-dependent damage to the bases in DNA in the presence of hydrogen peroxide. Biochem. J.273, 601–604 (1991).

    PubMed  Google Scholar 

  3. J. R. J. Sorenson,The anti-inflammatory activities of copper complexes. InMetal Ions in Biological Systems. (Ed. H. Sigel) pp. 77–124, Vol. 14, Marcel Dekker, New York 1982.

    Google Scholar 

  4. R. Milanino, A. Conforti, L. Franco, M. Marrella and G. P. Velo,Review: copper and inflammation — a possible rationale for the pharmacological manipulation of inflammatory disorders. Agents Actions16, 504–513 (1985).

    Article  PubMed  Google Scholar 

  5. A. J. Lewis,The role of copper in inflammatory disorders. Agents Actions15, 513–519 (1984).

    Article  PubMed  Google Scholar 

  6. R. Milanino, E. Passarella and G. P. Velo,Copper in the inflammatory process. InAdvances in Inflammation Research. (Eds. G. Weissmann, B. Samuelsson, and R. Paoletti) pp. 281–291, Vol. 1, Raven Press, New York 1979.

    Google Scholar 

  7. J. R. J. Sorenson, V. Kishore, A. Pezeshk, J. W. Oberley, S. W. C. Leuthauser and T. D. Oberley,Copper complexes: a physiological approach to the treatment of ‘Inflammatory diseases’. Inorg. Chim. Acta91, 285–294 (1984).

    Article  Google Scholar 

  8. Z. Korolkiewicz, E. Hac, I. Gagalo, P. Gorczyca and A. Lodzinska,The pharmacologic activity of complexes and mixtures with copper and salicylates or aminopyrine following oral dosing in rats. Agents Actions26, 355–359 (1989).

    Article  PubMed  Google Scholar 

  9. J. R. J. Sorenson,Copper chelates as possible active forms of antiarthritic agents. J. Med. Chem.19, 135–148 (1976).

    Article  PubMed  Google Scholar 

  10. J. R. J. Sorenson,Copper complexes, a unique class of anti-arthritic drugs. Prog. Med. Chem.15, 211–260 (1978).

    PubMed  Google Scholar 

  11. J. R. J. Sorenson,Copper complexes as the active metabolites of antiinflammatory agents. InInflammatory Diseases and Copper (Ed. J. R. J. Sorenson) pp. 289–301, The Humana Press, Clifton, New Jersey 1982.

    Google Scholar 

  12. L. R. De Alvare, K. Goda and T. Kimura,Mechanism of superoxide anion scavenging reaction by bis-(salicylato)-copper(II) complex. Biochem. Biophys. Res. Commun.69, 687–694 (1976).

    Article  PubMed  Google Scholar 

  13. U. Weser and L. M. Schubotz,Catalytic reaction of copper complexes and superoxide. InTrace Elements in the Pathogenesis and Treatment of Inflammation. (Eds. K. D. Rainsford, K. Brune and M. W. Whitehouse) pp. 103–120. Birkhäuser Verlag, Basel 1981.

    Google Scholar 

  14. C. Steinkühler, I. Mavelli, G. Melino, L. Rossi, U. Weser and G. Rotilio,Copper complexes with superoxide dismutatase activity enhance oxygen-mediated toxicity in human erythroleukemia cells. Ann. N.Y. Acad. Sci.551, 133–136 (1988).

    PubMed  Google Scholar 

  15. G. Czapski and S. Goldstein,The uniqueness of superoxide dismutase (SOD) — why cannot most copper compounds substitute SOD in vivo. Free Rad. Res. Comms.4, 225–229 (1988).

    Google Scholar 

  16. G. Czapski and S. Goldstein,Requirements for SOD mimics operating in vitro to work also in vivo. Free Rad. Res. Comms.12–13, 167–171 (1991).

    Google Scholar 

  17. J. M. C. Gutteridge and S. Wilkins,Copper salt-dependent hydroxyl radical formation damage to proteins actins as antioxidants. Biochim. Biophys. Acta759, 38–41 (1983).

    PubMed  Google Scholar 

  18. A. Samuni, M. Chevion and G. Czapski,Unusual copper-induced sensitization of the biological damage due to superoxide radicals. J. Biol. Chem.256, 12632–12635 (1981).

    PubMed  Google Scholar 

  19. J. M. McCord and E. D. Day,Superoxide-dependent production of hydroxyl radical catalyzed by iron-EDTA complex. FEBS Lett.86, 139–142 (1978).

    Article  PubMed  Google Scholar 

  20. D. A. Rowley and B. Halliwell,Superoxide-dependent and ascorbate-dependent formation of hydroxyl radicals in the presence of copper salts: a physiologically significant reactions? Arch. Biochem. Biophys.225, 279–284 (1983).

    Article  PubMed  Google Scholar 

  21. P. Saltman,Oxidative stress: a radical view. Sem. Hematol.26, 249–256 (1989).

    Google Scholar 

  22. M. B. Yim, P. B. Chock and E. R. Stadtman,Copper, zinc superoxide dismutase catalyzes hydroxyl radical production from hydrogen peroxide. Proc. Natl. Acad. Sci. USA87, 5006–5010 (1990).

    PubMed  Google Scholar 

  23. P. Maestre, L. Lambs, J.-P. Thouvenot and G. Berthon.Copper-ligand interactions and physiological free radical processes. Part 2. pH-dependent influence of Cu 2+ ions on Cu + -driven·OH generation (submitted).

  24. O. I. Aruoma,Oxidant scavenging and metal binding by anti-inflammatory drugs. InHandbook on Metal-Ligand Interactions in Biological Fluids. (Ed. G. Berthon) Vol. 1, Marcel Dekker, New York (in press).

  25. B. Halliwell and J. M. C. Gutteridge,Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem. J.219, 1–14 (1984).

    PubMed  Google Scholar 

  26. J. M. McCord,Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science185, 529–530 (1974).

    PubMed  Google Scholar 

  27. C. Beauchamp and I. Fridovich,A mechanism for the production of ethylene from methional. The generation of the hydroxyl radical by xanthine oxidase. J. Biol. Chem.245, 4641–4646 (1970).

    PubMed  Google Scholar 

  28. B. Halliwell,Superoxide-dependent formation of hydroxyl radicals in the presence of iron chelates. FEBS Lett.92, 321–326 (1978).

    Article  PubMed  Google Scholar 

  29. G. Czapski and Y. A. Ilan,On the generation of the hydroxylation agent from superoxide radical. Can the Haber-Weiss reactions be the source of OH radicals? Photochem. Photobiol.28, 651–653 (1978).

    Google Scholar 

  30. T. F. Slater,Free-radical mechanisms in tissue injury. Biochem. J.222, 1–15 (1984).

    PubMed  Google Scholar 

  31. J. R. J. Sorenson and V. Kishore,Antirheumatic activity of copper complexes. Trace Elem. Med.1, 93–102 (1984).

    Google Scholar 

  32. R. Milanino, A. Cassini, A. Conforti, L. Franco, M. Marella, U. Moretti and G. P. Velo,Copper and zinc status during acute inflammation: studies on blood, liver and kidneys metal levels in normal and inflamed rats. Agents Actions19, 215–223 (1986).

    Article  PubMed  Google Scholar 

  33. R. Milanino, M. Marella, U. Moretti, E. Concari and G. P. Velo,Copper and zinc status in rats with acute inflammation: focus on the inflamed area. Agents Actions24, 356–364 (1988).

    Article  PubMed  Google Scholar 

  34. V. Kishore,Effect of adjuvant arthritis on copper, zinc and iron metabolism in the rat. Res. Commun. Chem. Pathol. Pharm.63, 153–156 (1989).

    Google Scholar 

  35. P. Dore-Duffy, M. Peterson, F. Catalanotto, S. Marlow, S. Y. Ho, M. Ostrom and A. Weinstein,Zinc profiles in rheumatoid arthritis. Clin. Exp. Rheumatol.8, 541–546 (1990).

    PubMed  Google Scholar 

  36. M. C. Powanda,The role of leucocyte endogenous mediator (endogenous pyrogen) in inflammation. InInflammatory Diseases and Copper. (Ed. J. R. J. Sorenson) pp. 31–43, The Humana Press, Clifton, NJ 1982.

    Google Scholar 

  37. J. Néve, J. Fontaine, A. Peretz and J. P. Famayer,Changes in zinc, copper and selenium status during adjuvant-induced arthritis in rats. Agents Actions25, 146–155 (1988).

    Article  PubMed  Google Scholar 

  38. P. G. Winyard, H. Pall, J. Lunec and D. R. Blake,Nonceruloplasmin-bound copper (‘phenanthroline copper’) is not detectable in fresh serum or synovial fluid from patients with rheumatoid arthritis. Biochem. J.247, 245–246 (1987).

    PubMed  Google Scholar 

  39. J. Gutteridge,Non-ceruloplasmin copper and the phenanthroline assay. Biochem. J.247, 246–247 (1987).

    Google Scholar 

  40. A. Conforti, L. Franco, T. Milanino, A. Totorizzo and G. P. Velo,Copper metabolism during acute inflammation: studies on liver and serum copper concentrations in normal and inflamed rats. Br. J. Pharmacol.79, 45–52 (1983).

    PubMed  Google Scholar 

  41. R. P. Agarwal and D. D. Perrin,Computer-based approach to chelation therapy: a theoretical study of some chelating agents for the selective removal of toxic metal ions from plasma. Agents Actions6/5, 667–673 (1976).

    Article  Google Scholar 

  42. S. H. Laurie and E. S. mohammed,The influence of l -cysteine on the exchangeable copper in blood plasma. Inorg. Chim. Acta55, L63-L66 (1981).

    Article  Google Scholar 

  43. P. M. May and D. R. Williams,Role of low molecular weight complexes in the control of rheumatoid arthritis. InMetal Ions in Biological Systems. (Ed. H. Sigel) pp. 283–317, Vol. 12, Marcel Dekker, New York 1981.

    Google Scholar 

  44. G. Berthon, B. Hacht, M.-J. Blais and P. M. May,Copperhistidine ternary complex equilibria with glutamine, asparagine and serine. The implications for computer-simulated distributions of copper(II) in blood plasma. Inorg. Chim. Acta125, 219–227 (1986).

    Article  Google Scholar 

  45. P. M. May, P. W. Linder and D. R. Williams,Computer simulation of metal-ion equilibria in biofluids: Models for the low-molecular-weight complex distribution of calcium(II), magnesium(II), manganese(II), iron(III), copper(II), zinc(II), and lead(II) ions in human blood plasma. J. Chem. Soc. Dalton Trans. 588–595 (1977).

  46. D. M. Miller, G. R. Buettner and S. D. Aust,Transition metals as catalysts of “autoxidation” reactions. Free Rad. Biol. Med.8, 95–108 (1990).

    Article  PubMed  Google Scholar 

  47. B. Halliwell,Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. FEBS Lett.96, 238–242 (1978).

    Article  PubMed  Google Scholar 

  48. J. M. C. Gutteridge, R. Richmond and B. Halliwell,Inhibition of iron-catalyzed hydroxyl radical formation and of lipid peroxidation by desferrioxamine. Biochem. J.184, 469–472 (1979).

    PubMed  Google Scholar 

  49. J. M. C. Gutteridge,Reactivity of hydroxyl and hydroxyl-like radicals discriminated by release of thiobarbituric acid-reactive material from deoxy sugars, nucleosides and benzoate. Biochem. J.224, 761–767 (1984).

    PubMed  Google Scholar 

  50. O. I. Aruoma and B. Halliwell,The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs. Xenobiotica18, 459–470 (1988).

    PubMed  Google Scholar 

  51. J. B. Smith, J. C. Cusumano and C. F. Babbs,Quantitative effects of iron chelators of hydroxyl radical production by the superoxide-driven Fenton reaction. Free Rad. Res. Comms.8, 101–106 (1990).

    Google Scholar 

  52. J. M. C. Gutteridge,Ferrous-salt-promoted damage to deoxyribose and benzoate. Biochem. J.243, 709–714 (1987).

    PubMed  Google Scholar 

  53. J. M. C. Gutteridge,Free radical formation and antioxidant protection in extracellular fluids. InFree Radicals, Lipo-proteins, and Membrane Lipids. (Eds. A. Crastes de Paulet et al.) pp. 371–379, Plenum Press, New York 1990.

    Google Scholar 

  54. S. L. Marklund, A. Bjelle and L. G. Elmqvist,Superoxide dismutase isoenzymes of the synovial fluid in rheumatoid arthritis and in reactive arthritides. Ann. Rheum. Dis.45, 847–851 (1986).

    PubMed  Google Scholar 

  55. D. Klug, J. Rabani and I. Fridovich,A direct demonstration of the catalytic action of superoxide dismutase through the use of pulse radiolysis. J. Biol. Chem.247, 4839–4842 (1972).

    PubMed  Google Scholar 

  56. C. Steinkühler, G. Rotilio and U. Weser,Copper complexes and free radicals. InHandbook on Metal-Ligand Interactions in Biological Fluids. (Ed. G. Berthon) Vol. 2, Marcel Dekker, New York (in press).

  57. W. M. Willingham and J. R. J. Sorenson,Physiologic role of copper complexes in neoplasia. Trace Elem. Med.3, 139–152 (1986).

    Google Scholar 

  58. J. R. J. Sorenson (Ed.) Inflammatory Diseases and Copper, The Humana Press, Clifton, NJ 1982.

    Google Scholar 

  59. J. R. J. Sorenson (Ed.) Biology of Copper Complexes. The Humana Press, Clifton, New Jersey 1987.

    Google Scholar 

  60. I. Emerit, L. Packer and C. Auclair (Eds.) Antioxidants in Therapy and Preventive Medicine, Plenum Press, New York 1990.

    Google Scholar 

  61. K. R. Huber, R. Sridhar, E. H. Griffith, E. L. Amma and J. Roberts,Superoxide dismutase-like activities of copper(II) comlexes tested in serum. Biochim. Biophys. Acta915, 267–276 (1987).

    PubMed  Google Scholar 

  62. J. R. J. Sorenson, L. W. Oberley, R. K. Crouch, T. W. Kensler, V. Kishore, S. W. C. Leuthauser, T. D. Oberley and A. Pezeshk,Pharmacological activities of copper compounds in chronic diseases. Biol. Tr. Elem. Res.5, 257–273 (1983).

    Google Scholar 

  63. I. Fridovich,The biology of oxygen radicals. Science201, 875–880 (1978).

    PubMed  Google Scholar 

  64. P. Maestre, L. Lambs, J.-P. Thouvenot and G. Berthon,Copper-ligand interactions and physiological free radical processes. pH-dependent influence of Cu 2+ ions on Fe 2+ -driven OH generation. Free Rad. Res. Comms.15, 305–317 (1992).

    Google Scholar 

  65. A. E. Martell (Ed.) Development of Iron Chelators for Clinical Use, Elsevier, New York 1981.

    Google Scholar 

  66. T. Ozawa, A. Hanaki and K. Onodera,Copper(II) ethylenediaminetetraacetate complex does activate hydrogen peroxide in the presence of biological reductants. Biochem. Int.24, 661–667 (1991).

    PubMed  Google Scholar 

  67. B. Halliwell, J. M. C. Gutteridge and D. BlakeMetal ions and oxygen radical reactions in human inflammatory joint disease. Phil. Trans. R. Soc. Lond.B311, 659–671 (1985).

    Google Scholar 

  68. B. Halliwell, J. R. Hoult and D. R. Blake,Oxidants, inflammation, and anti-inflammatory drugs. FASEB J.2, 2867–2873 (1988).

    PubMed  Google Scholar 

  69. G. E. Jackson, P. M. May and D. R. Williams,Metal-ligand complexes involved in rheumatoid arthritis-I. Justifications for copper administration. J. Inorg. Nucl. Chem.40, 1189–1194 (1978).

    Article  Google Scholar 

  70. G. B. West,Some anti-inflammatory activities of copper complexes of amino acids. Inter. Archs Allergy Appl. Immun.66, 110–113 (1981).

    Google Scholar 

  71. H. M. Darwish, J. C. Cheney, R. C. Schmitt and M. J. Ettinger,Mobilization of copper(II) from plasma compoments and mechanism of hepatic copper transport. Amer. J. Physiol.246, G72-G79 (1984).

    PubMed  Google Scholar 

  72. G. Carlin, R. Djursäter and B. Gerdin,SOD-like activity of copper-histidine. Acta Physiol. Scand.124 S542, 414 (1985).

    Google Scholar 

  73. P. Tachon,DNA single strand breakage by H 2 O 2 and ferric or cupric ions: its modulation by histidine. Free Rad. Res. Comms.9, 39–47 (1990).

    Google Scholar 

  74. I. L. Bonta, M. J. Parnham, J. E. Vincent and P. C. Bragt,Anti-rheumatic drugs: present deadlock and new vista. InProgress in Medicinal Chemistry. (Eds. G. P. Ellis and G. B. West) pp. 186–273, Elsevier, New York 1980.

    Google Scholar 

  75. V. Brumas and G. Berthon,Speciation studies on the copper-salicylate system in relation to its antiinflammatory activity. InMetal Ions in Biology and Medicine. (Eds. P. Collery, L. A. Poirier, M. Manfait and J.-C. Etienne) pp. 5–7, John Libbey Eurotext, London 1989.

    Google Scholar 

  76. V. Brumas and G. Berthon,Copper(II) interactions with some non-steroidal antiinflammatory drugs in relation to their potential role in the treatment of inflammation. J. Inorg. Biochem.43, 626 (1991).

    Article  Google Scholar 

  77. R. M. Smith and A. E. Martell (Eds.) Critical Stability Constants, Vol. 6, Plenum Press, New York 1989.

    Google Scholar 

  78. P. M. Hanna and R. P. Mason,Direct evidence for inhibition of free radical formation from Cu(I) and hydrogen peroxide by glutathione and other potential ligands using the EPR spin-trapping technique. Arch. Biochem. Biophys.295, 205–213 (1992).

    Article  PubMed  Google Scholar 

  79. P. M. May, D. R. Williams and P. W. Linder,Biological significance of low molecular weight iron(III) complexes. InMetal Ions in Biological Systems (Ed. H. Sigel) pp. 29–76, Vol. 7, Marcel Dekker, New York 1978.

    Google Scholar 

  80. G. E. Jackson, P. M. May and D. R. WilliamsMetal-ligand complexes involved in rheumatoid arthritis-VI. Computer models simulating the low molecular weight complexes present in blood plasma for normal and arthritic individuals. J. Inorg. Nucl. Chem.40, 1127–1234 (1978).

    Google Scholar 

  81. G. E. Jackson and M. J. Kelly,Copper anti-inflammatory drugs in rheumatoid arthritis. Part 1. Computer aided drug design. Inorg. Chim. Acta152, 215–217 (1988).

    Article  Google Scholar 

  82. G. J. Quinlan and J. M. C. Gutteridge,Hydroxyl radical generation by the tetracycline antibiotics with free radical damage to DNA, lipids and carbohydrate in the presence of iron and copper. Free Rad. Biol. Med.5, 341–348 (1988).

    Article  PubMed  Google Scholar 

  83. G. J. Quinlan and J. M. C. Gutteridge,Oxidative damage to DNA and deoxyribose by β-lactam antibiotics in the presence of iron and copper salts. Free Rad. Res. Comms.5, 149–158 (1988).

    Google Scholar 

  84. K. Radtke, R. Byrnes, F. Lornitzo, W. E. Antholine and D. H. Petering,Requirements of intracellular iron for the mechanism of action of bleomycin and hydrogen peroxide. J. Inorg. Biochem.43, 456 (1991).

    Article  Google Scholar 

  85. J. H. DoroshowPrevention of doxorubicin-induced killing of MCF-7 human breast cancer cells by oxygen radical scavengers and iron chelating agents. Biochem. Biophys. Res. Comm.135, 330–335 (1986).

    Article  PubMed  Google Scholar 

  86. Y. Sugiura, T. Takita and H. Umezawa,Bleomycin antibiotics: Metal complexes and their biological action. InMetal Ions in Biological Systems (Ed. H. Sigel) pp. 81–108, Vol. 19, Marcel Dekker, New York 1985.

    Google Scholar 

  87. P. M. May,Agents acting on passive ion transport. InComprehensive Medicinal Chemistry, Vol. II, Pergamon Press, New York 1989.

    Google Scholar 

  88. B. B. Hasinoff, J. P. Cavey and P. J. O'Brien,The adriamycin (doxorubicin)-induced inactivation of cytochrome c oxidase depends on the presence of iron or copper. Xenobiotica19, 231–241 (1989).

    PubMed  Google Scholar 

  89. I. Hesslewood, W. Cramp, D. McBrien, P. Williamson and K. Lott,Copper as a hypoxic cell sensitizer of mammalian cells. Br. J. Cancer37 (Suppl. III), 95–97 (1978).

    Google Scholar 

  90. J. A. O'Hara, E. B. Douple, M. J. Abrams, C. M. Giandomenico, F. C. Bradley, M. A. McElligott and F. S. Caruso,Combined modality treatment with ternary Cu(II) complexes and X rays. Int. J. Radiation Oncology Biol. Phys.22, 607–612 (1992).

    Google Scholar 

  91. B. Halliwell,Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Rad. Biol. Med.7, 645–651 (1989).

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. INSERM U305, Equipe “Bioréactifs: Spéciation et Biodisponibilité”, 38 rue des Trente-six Ponts, 31400, Toulouse, France

    G. Berthon

Authors
  1. G. Berthon
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berthon, G. Is copper pro- or anti-inflammatory? A reconciling view and a novel approach for the use of copper in the control of inflammation. Agents and Actions 39, 210–217 (1993). https://doi.org/10.1007/BF01998975

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01998975

Keywords

Search

Navigation