Neuzil J, Witting P K, Stocker R
Biochemistry Unit, The Heart Research Institute, 145 Missenden Road, Camperdown, NSW 2050, Australia.
Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):7885-90. doi: 10.1073/pnas.94.15.7885.
As the oxidation of low density lipoprotein (LDL) lipids may be a key event in atherogenesis, there is interest in antioxidants as potential anti-atherogenic compounds. Here we report that alpha-tocopheryl hydroquinone (alpha-TQH2) strongly inhibited or completely prevented the (per)oxidation of ubiquinol-10 (CoQ10H2), alpha-tocopherol (alpha-TOH), and both surface and core lipids in LDL exposed to either aqueous or lipophilic peroxyl radicals, Cu2+, soybean lipoxygenase, or the transition metal-containing Ham's F-10 medium in the absence or presence of human monocyte-derived macrophages. The antioxidant activity of alpha-TQH2 was superior to that of several other lipophilic hydroquinones, including endogenous CoQ10H2, which is regarded as LDL's first line of antioxidant defence. At least three independent activities contributed to the antioxidant action of alpha-TQH2. First, alpha-TQH2 readily associated with LDL and instantaneously reduced the lipoprotein's ubiquinone-10 to CoQ10H2, thereby maintaining this antioxidant in its active form. Second, alpha-TQH2 directly intercepted aqueous peroxyl radicals, as indicated by the increased rate of its consumption with increasing rates of radical production, independent of LDL's content of CoQ10H2 and alpha-TOH. Third, alpha-TQH2 rapidly quenched alpha-tocopheroxyl radical in oxidizing LDL, as demonstrated directly by electron paramagnetic resonance spectroscopy. Similar antioxidant activities were also seen when alpha-TQH2 was added to high-density lipoprotein or the protein-free Intralipid, indicating that the potent antioxidant activity of alpha-TQH2 was neither lipoprotein specific nor dependent on proteins. These results suggest that alpha-TQH2 is a candidate for a therapeutic lipid-soluble antioxidant. As alpha-tocopherylquinone is formed in vivo at sites of oxidative stress, including human atherosclerotic plaque, and biological systems exist that reduce the quinone to the hydroquinone, our results also suggest that alpha-TQH2 could be a previously unrecognized natural antioxidant.
由于低密度脂蛋白（LDL）脂质的氧化可能是动脉粥样硬化发生过程中的关键事件，人们对作为潜在抗动脉粥样硬化化合物的抗氧化剂产生了兴趣。在此我们报告，α-生育酚氢醌（α-TQH2）能强烈抑制或完全阻止泛醇-10（CoQ10H2）、α-生育酚（α-TOH）以及暴露于水性或亲脂性过氧自由基、Cu2+、大豆脂氧合酶或含过渡金属的哈姆氏F-10培养基中的LDL表面和核心脂质的（过）氧化，无论是否存在人单核细胞衍生的巨噬细胞。α-TQH2的抗氧化活性优于其他几种亲脂性氢醌，包括内源性CoQ10H2，后者被视为LDL抗氧化防御的第一道防线。至少有三种独立的活性促成了α-TQH2的抗氧化作用。首先，α-TQH2很容易与LDL结合，并立即将脂蛋白的泛醌-10还原为CoQ10H2，从而使这种抗氧化剂保持其活性形式。其次，α-TQH2直接拦截水性过氧自由基，这表现为随着自由基产生速率的增加，其消耗速率也增加，且与LDL中CoQ10H2和α-TOH的含量无关。第三，α-TQH2能迅速淬灭氧化LDL中的α-生育酚自由基，电子顺磁共振光谱直接证明了这一点。当将α-TQH2添加到高密度脂蛋白或无蛋白的英脱利匹特中时，也观察到了类似的抗氧化活性，这表明α-TQH2强大的抗氧化活性既不是脂蛋白特异性的，也不依赖于蛋白质。这些结果表明，α-TQH2是一种治疗性脂溶性抗氧化剂的候选物。由于α-生育醌在体内氧化应激部位形成，包括人类动脉粥样硬化斑块，并且存在将醌还原为氢醌的生物系统，我们的结果还表明，α-TQH2可能是一种以前未被认识的天然抗氧化剂。
