When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid

The inclusion of uric acid in the incubation medium during copper-induced l ow-density lipoprotein (LDL) oxidation exerted either an antioxidant or pro -oxidant effect. The pro-oxidant effect, as mirrored by an enhanced formati on of conjugated dienes, lipid peroxides, thiobarbituric acid-reactive subs tances and increase in negative charge, occurred when uric acid was added l ate during the inhibitory or lag phase and during the subsequent extensive propagation phase of copper-stimulated LDL oxidation. The pro-oxidant effec t of uric acid was specific for copper-induced LDL oxidation and required t he presence of copper as either Cu(I) or Cu(II). In addition, it became muc h more evident when the copper to LDL molar ratio was below a threshold val ue of approx. 50. In native LDL, the shift between the antioxidant and the pro-oxidant activities was related to the availability of lipid hydroperoxi des formed during the early phases of copper-promoted LDL oxidation. The ar tificial enrichment of isolated LDL with alpha-tocopherol delayed the onset of the pro-oxidant activity of uric acid and also decreased the rate of st imulated lipid peroxidation. However, previous depletion of alpha-tocophero l was not a prerequisite for unmasking the prooxidant activity of uric acid , since this became apparent even when cc-tocopherol was still present in s ignificant amounts (more than 50% of the original values) in LDL. These res ults suggest, irrespective of the levels of endogenous alpha-tocopherol, th at uric acid may enhance LDL oxidation by reducing Cu(II) to Cu(I), thus ma king more Cu(I) available for subsequent radical decomposition of lipid per oxides and propagation reactions.