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Anti‐ and pro‐oxidant effects of urate in copper‐induced low‐density lipoprotein oxidation

2002; Wiley; Volume: 269; Issue: 22 Linguagem: Inglês

10.1046/j.1432-1033.2002.03245.x

1432-1033

Paulo Filipe, Josiane Haigle, João Freitas, Afonso Fernandes, Jean‐Claude Mazière, Cécile Mazière, René Santús, Patrice Morlière,

Gout, Hyperuricemia, Uric Acid

We reported earlier that urate may behave as a pro‐oxidant in Cu 2+ ‐induced oxidation of diluted plasma. Thus, its effect on Cu 2+ ‐induced oxidation of isolated low‐density lipoprotein (LDL) was investigated by monitoring the formation of malondialdehyde and conjugated dienes and the consumption of urate and carotenoids. We show that urate is antioxidant at high concentration but pro‐oxidant at low concentration. Depending on Cu 2+ concentration, the switch between the pro‐ and antioxidant behavior of urate occurs at different urate concentrations. At high Cu 2+ concentration, in the presence of urate, superoxide dismutase and ferricytochrome c protect LDL from oxidation but no protection is observed at low Cu 2+ concentration. The use of Cu 2+ or Cu + chelators demonstrates that both copper redox states are required. We suggest that two mechanisms occur depending on the Cu 2+ concentration. Urate may reduce Cu 2+ to Cu + , which in turn contributes to formation. The Cu 2+ reduction is likely to produce the urate radical (UH ·– ). It is proposed that at high Cu 2+ concentration, the reaction of UH ·– radical with generates products or intermediates, which trigger LDL oxidation. At low Cu 2+ concentration, we suggest that the Cu + ions formed reduce lipid hydroperoxides to alkoxyl radicals, thereby facilitating the peroxidizing chain reaction. It is anticipated that these two mechanisms are the consequence of complex LDL–urate–Cu 2+ interactions. It is also shown that urate is pro‐oxidant towards slightly preoxidized LDL, whatever its concentration. We reiterate the conclusion that the use of antioxidants may be a two‐edged sword.