Speciation 98: Abstracts

The role of copper with respect to inflammation is not straightforward. On the one hand, copper displays antiinflammatory properties.¹ Copper complexes of inactive substances are more active than inorganic copper salts, and copper complexes of nonsteroidal antiinflammatory drugs (NSAIDs) are more effective than the parent substances. Based on these observations, Sorenson has proposed that copper complexes of NSAIDs are their active metabolites. ¹ On the other hand, copper can, like iron, trigger Fenton-type reactions in vivo. Attention has even been drawn to the potential risk of its therapeutic use in this context.²

A priori, the fact that copper can behave both as an antiinflammatory and a pro-oxidant agent may seem paradoxical. However, the paradox becomes only apparent if one considers that copper-mediated Fenton chemistry may induce different effects in vivo depending on the nature of the ligand(s) bound to the Cu²⁺ ions acting as catalysts in the Haber-Weiss reaction.³ In order to reconcile these two apparent conflicting roles, the notion of ^.OH-inactivating ligand (OIL) has recently been proposed, which defines any chemical agent capable of (i) specifically binding metal ions involved in ^.OH formation, (ii) maintaining the redox activity of these metal ions in their resulting complexes, and (iii) quickly reacting with the ^.OH formed to give rise to innocuous metabolites.³

The first criterion to be met for a ligand to be regarded as a potential copper OIL is to mobilise a significant fraction of copper at the inflammatory site. A comparison between copper-activated inactive substances and copper-potentiated NSAIDs in respect of this property was in order to test Sorenson's above hypothesis.¹ Any significant difference in the copper mobilising capacity of these two classes of compounds would indeed call this hypothesis into question. Salicylate, used as reference NSAID, was first investigated using computer-aided speciation, and was found to bind a negligible fraction of copper at any pH in vivo. In other words, salicylate cannot behave as an effective OIL.⁴ Anthranilate, an inactive substance activated by copper, was shown to mobilise an even lesser fraction of copper than salicylate at pH 7.4, but, in contrast to salicylate, is expected to bind increasing fractions of copper as the pH decreasesi.e., as inflammation grows. Anthranilate may therefore be considered as a potential OIL.⁵ Based on these results, copper potentiation of NSAIDs appears to be independent of any Cu-NSAID interactionwhich effectively questions Sorenson's above hypothesis whereas copper activation of inactive substances seems to be due to copper mobilisation by these substances at inflammatory sites.

The second requirement for a ligand to be considered as a potential copper OIL is to reduce the amount of copper-induced hydroxyl radicals detected in the body of a solution as a function of its capacity to bind copper. The same compounds were tested in this respect, using deoxyribose as a detector in solutions whose compositions were designed by speciation. The well-known capacity of salicylate to scavenge ^.OH radicals was found to be independent of its degree of association with copper. In contrast, anthranilate reduction of the detected amount of ^.OH radicals was found to be in direct relation with the percentage of copper bound to anthranilate.⁶ These observations, which are perfectly in line with the above results, suggest that the phenomenon that lies behind NSAID copper potentiation is different from that leading to copper activation of inactive substances. (Parallel investigations suggest that the apparent copper potentiation of NSAIDS may be due to copper interactions with endogenous histidine.)

Allowance being made to the influence of ligands on the redox potential of the Cu(II)/Cu(I) couple in the above reactions, the present results provide a beginning of rationale to the antiinflammatory activity of copper complexes, and pave the way for new research strategies on the use of copper in the regulation of inflammation.

References

1. J.R.J. Sorenson, J. Med. Chem. 19, 135 (1976).
2. O.I. Aruoma, in Handbook of Metal-Ligand Interactions in Biological Fluids; Bioinorganic Medicine, Vol. 2, G. Berthon, Ed., Marcel Dekker, New York, 1995, p. 910.
3. G. Berthon, Agents Actions 39, 210 (1993).
4. 4. V. Brumas, B. Brumas and G. Berthon, J. Inorg. Biochem. 57, 191 (1995).
5. H. Miche, V. Brumas and G. Berthon, J. Inorg. Biochem. 68, 27 (1997).
6. S. Gaubert, L. Lambs and G. Berthon, in Therapeutic Uses of Trace Elements, J. Nève, P. Chappuis and M. Lamand, Eds., Plenum Press, New York, 1996, p. 139.

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