Filipe Paulo, Haigle Josiane, Freitas João, Fernandes Afonso, Mazière Jean-Claude, Mazière Cécile, Santus René, Morlière Patrice
Centro de Metabolismo e Endocrinologia, Faculdade de Medicina de Lisboa, Portugal.
Eur J Biochem. 2002 Nov;269(22):5474-83. doi: 10.1046/j.1432-1033.2002.03245.x.
We reported earlier that urate may behave as a pro-oxidant in Cu2+-induced oxidation of diluted plasma. Thus, its effect on Cu2+-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 Cu2+ concentration, the switch between the pro- and antioxidant behavior of urate occurs at different urate concentrations. At high Cu2+ concentration, in the presence of urate, superoxide dismutase and ferricytochrome c protect LDL from oxidation but no protection is observed at low Cu2+ concentration. The use of Cu2+ or Cu+ chelators demonstrates that both copper redox states are required. We suggest that two mechanisms occur depending on the Cu2+ concentration. Urate may reduce Cu2+ to Cu+, which in turn contributes to formation. The Cu2+ reduction is likely to produce the urate radical (UH.-). It is proposed that at high Cu2+ concentration, the reaction of UH.- radical with generates products or intermediates, which trigger LDL oxidation. At low Cu2+ 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-Cu2+ 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.
我们之前报道过，尿酸在铜离子诱导的稀释血浆氧化过程中可能表现为促氧化剂。因此，通过监测丙二醛和共轭二烯的形成以及尿酸和类胡萝卜素的消耗，研究了其对铜离子诱导的分离低密度脂蛋白（LDL）氧化的影响。我们发现，尿酸在高浓度时是抗氧化剂，但在低浓度时是促氧化剂。根据铜离子浓度的不同，尿酸促氧化和抗氧化行为之间的转变发生在不同的尿酸浓度下。在高铜离子浓度下，存在尿酸时，超氧化物歧化酶和铁细胞色素c可保护低密度脂蛋白不被氧化，但在低铜离子浓度下未观察到保护作用。使用铜离子或亚铜离子螯合剂表明两种铜的氧化态都是必需的。我们认为，根据铜离子浓度会出现两种机制。尿酸可能将铜离子还原为亚铜离子，这反过来又有助于形成。铜离子的还原很可能产生尿酸自由基（UH·）。有人提出，在高铜离子浓度下，UH·自由基与反应生成产物或中间体，从而引发低密度脂蛋白氧化。在低铜离子浓度下，我们认为形成的亚铜离子将脂质氢过氧化物还原为烷氧基自由基，从而促进过氧化链式反应。预计这两种机制是复杂的低密度脂蛋白 - 尿酸 - 铜离子相互作用的结果。还表明，无论尿酸浓度如何，尿酸对轻度预氧化的低密度脂蛋白都是促氧化剂。我们重申抗氧化剂的使用可能是一把双刃剑这一结论。
