Copper-Aspirin Complex Inhibits Cyclooxygenase-2 More Selectively than Aspirin

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The antiinflammatory effects of the copper-aspirin complex (Cu-Asp) were more potent than that of Asp in rats or mice with fewer classic adverse effects. The aim of this study was to determine the cause by evaluating Cu-Asp selective inhibition on cyclooxygenases (COX). COX-1 inhibition was evaluated based on 6-keto-prostaglandin F_<1α> (6-keto-PGF_<1α>) in an endothelial cell model, and COX-2 inhibition was based on prostaglandin E_2 (PGE_2) in a macrophage model. Radioimmunoassay (RIA) was applied to determine 6-keto-PGF_<1α> in resting human umbilical vein endothelial cell line (ECV304), and PGE_2 in activated macrophages. The results showed that the inhibition of 6-keto-PGF_<1α> yield by Cu-Asp (3 to 0.01mM) was markedly weaker than that by aspirin (Asp); while the inhibition of PGE_2 yield by Cu-Asp (10 to 0.1mM) was significantly stronger than that by Asp. Based on the inhibition on 6-keto-PGF_<1α> and PGE_2, the medium inhibitory concentration (IC_<50>) of Cu-Asp on COX-1 and on COX-2 was 1.03±0.15mM, and 0.32±0.04mM, respectively. The selective inhibition index on COX-2, IC_<50> (COX-1)/IC_<50> (COX-2), of Cu-Asp was 3.33±0.89, while that of Asp was 0.42±0.12. The results suggest that, unlike Asp, Cu-Asp is a relatively selective inhibitor of COX-2 in the present models; the selectivity of Cu-Asp is about seven-fold greater than that of Asp.
公益社団法人日本薬学会の論文
2007-11-01