INHIBITION OF COPPER-INDUCED AND PEROXYL RADICAL-INDUCED LDL LIPID OXIDATION BY EBSELEN - ANTIOXIDANT ACTIONS IN ADDITION TO HYDROPEROXIDE-REDUCING ACTIVITY

The effects of ebselen (2-phenyl-1,2-benzisoselenazol-3(2H)-one) on hu man LDL lipid oxidation induced by different fluxes of aqueous peroxyl radicals and cupric ion (at a Cu2+:LDL ratio of 17:1) were investigat ed. Addition of ebselen to LDL oxidised with Cu2+ prolonged the durati on of the lag-phase typical for this oxidising condition, with the inc rease being proportional to the square of the ebselen concentration. E bselen also prevented the formation of lipid hydroperoxides and inhibi ted the consumption of endogenous antioxidants during the early period of Cu2+-induced oxidation, during which time the drug was converted s toichiometrically into ebselen oxide 2-phenyl-1,2-benzisoselenazol-3(2 H)-one-Se-oxide). Ebselen oxide itself was antioxidant inactive. Ebsel en also inhibited formation of lipid-hydroperoxides and spared alpha-t ocopherol during the initial stages of LDL oxidation mediated by low-f lux of aqueous peroxyl radicals, where a lag-phase was not observed. W hen a higher flux of aqueous peroxyl radicals was used, ebselen increa sed the observed inhibited phase of peroxidation in a dose-dependent m anner, though less pronounced than its prolongating effect on the lag- phase of Cu2+-induced LDL lipid oxidation. Ebselen was also able to di rectly interact with Cu1+, alkyl peroxyl radicals and alpha-tocopherox yl radicals, demonstrating that the drug has a number of potential ant ioxidant activities in addition to its well-known hydroperoxide-reduci ng activity. We conclude that the antioxidant activities of ebselen ar e complex and that their relative importance likely vary depending on the experimental system used.