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.
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J. R. J. Sorenson,Copper complexes offer a physiological approach to treatment of chronic diseases. Prog. Med. Chem.26, 437–568 (1989).
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).
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.
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).
A. J. Lewis,The role of copper in inflammatory disorders. Agents Actions15, 513–519 (1984).
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.
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).
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).
J. R. J. Sorenson,Copper chelates as possible active forms of antiarthritic agents. J. Med. Chem.19, 135–148 (1976).
J. R. J. Sorenson,Copper complexes, a unique class of anti-arthritic drugs. Prog. Med. Chem.15, 211–260 (1978).
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.
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).
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.
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).
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).
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).
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).
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).
J. M. McCord and E. D. Day,Superoxide-dependent production of hydroxyl radical catalyzed by iron-EDTA complex. FEBS Lett.86, 139–142 (1978).
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).
P. Saltman,Oxidative stress: a radical view. Sem. Hematol.26, 249–256 (1989).
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).
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).
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).
B. Halliwell and J. M. C. Gutteridge,Oxygen toxicity, oxygen radicals, transition metals and disease. Biochem. J.219, 1–14 (1984).
J. M. McCord,Free radicals and inflammation: protection of synovial fluid by superoxide dismutase. Science185, 529–530 (1974).
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).
B. Halliwell,Superoxide-dependent formation of hydroxyl radicals in the presence of iron chelates. FEBS Lett.92, 321–326 (1978).
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).
T. F. Slater,Free-radical mechanisms in tissue injury. Biochem. J.222, 1–15 (1984).
J. R. J. Sorenson and V. Kishore,Antirheumatic activity of copper complexes. Trace Elem. Med.1, 93–102 (1984).
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).
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).
V. Kishore,Effect of adjuvant arthritis on copper, zinc and iron metabolism in the rat. Res. Commun. Chem. Pathol. Pharm.63, 153–156 (1989).
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).
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.
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).
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).
J. Gutteridge,Non-ceruloplasmin copper and the phenanthroline assay. Biochem. J.247, 246–247 (1987).
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).
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).
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).
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.
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).
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).
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).
B. Halliwell,Superoxide-dependent formation of hydroxyl radicals in the presence of iron salts. FEBS Lett.96, 238–242 (1978).
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).
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).
O. I. Aruoma and B. Halliwell,The iron-binding and hydroxyl radical scavenging action of anti-inflammatory drugs. Xenobiotica18, 459–470 (1988).
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).
J. M. C. Gutteridge,Ferrous-salt-promoted damage to deoxyribose and benzoate. Biochem. J.243, 709–714 (1987).
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.
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).
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).
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).
W. M. Willingham and J. R. J. Sorenson,Physiologic role of copper complexes in neoplasia. Trace Elem. Med.3, 139–152 (1986).
J. R. J. Sorenson (Ed.) Inflammatory Diseases and Copper, The Humana Press, Clifton, NJ 1982.
J. R. J. Sorenson (Ed.) Biology of Copper Complexes. The Humana Press, Clifton, New Jersey 1987.
I. Emerit, L. Packer and C. Auclair (Eds.) Antioxidants in Therapy and Preventive Medicine, Plenum Press, New York 1990.
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).
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).
I. Fridovich,The biology of oxygen radicals. Science201, 875–880 (1978).
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).
A. E. Martell (Ed.) Development of Iron Chelators for Clinical Use, Elsevier, New York 1981.
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).
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).
B. Halliwell, J. R. Hoult and D. R. Blake,Oxidants, inflammation, and anti-inflammatory drugs. FASEB J.2, 2867–2873 (1988).
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).
G. B. West,Some anti-inflammatory activities of copper complexes of amino acids. Inter. Archs Allergy Appl. Immun.66, 110–113 (1981).
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).
G. Carlin, R. Djursäter and B. Gerdin,SOD-like activity of copper-histidine. Acta Physiol. Scand.124 S542, 414 (1985).
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).
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.
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.
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).
R. M. Smith and A. E. Martell (Eds.) Critical Stability Constants, Vol. 6, Plenum Press, New York 1989.
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).
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.
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).
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).
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).
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).
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).
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).
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.
P. M. May,Agents acting on passive ion transport. InComprehensive Medicinal Chemistry, Vol. II, Pergamon Press, New York 1989.
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).
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).
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).
B. Halliwell,Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Rad. Biol. Med.7, 645–651 (1989).
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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
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- Physiological Activity