Iuliano L, Pedersen J Z, Camastra C, Bello V, Ceccarelli S, Violi F
Institute of Clinical Medicine I, University La Sapienza, Rome, Italy.
Free Radic Biol Med. 1999 Apr;26(7-8):858-68. doi: 10.1016/s0891-5849(98)00271-8.
The oxidative modification of low density lipoprotein (LDL) is thought to be an important factor in the initiation and development of atherosclerosis. Antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Potent synthetic antioxidants are currently being tested, but they are not necessarily safe for human use. We here characterize the antioxidant activity of IRFI005, the active metabolite of Raxofelast (IRFI0016) that is a novel synthetic analog of vitamin E under clinical development, and demonstrate that it prevents oxidative modification of LDL. IFI005 inhibited the oxidative modification of LDL, measured through the generation of MDA, electrophoretic mobility and apo B100 fluorescence. During the oxidation process IRF1005 was consumed with the formation of the benzoquinone oxidation product. The powerful antioxidant activity of IRFI005 is at least in part mediated by a chain breaking mechanism as it is an efficient peroxyl radical scavenger with a rate constant k(IRFI005 + LOO(o)) of 1.8 X 10(6) M(-1)s(-1). 4. IRFI005 substantially preserved LDL-associated antioxidants, alpha-tocopherol and carotenoids, and when co-incubated with physiologic levels of ascorbate provoked a synergistic inhibition of LDL oxidation. Also the co-incubation of IRFI005 with Trolox caused a synergistic effect, and a lag phase in the formation of the trolox-benzoquinone oxidation product. A synergistic inhibition of lipid peroxidation was also demonstrated by co-incubating IRFI005 and alpha-tocopherol incorporated in linoleic acid micelles. These data strongly suggest that IRFI005 can operate by a recycling mechanism similar to the vitamin E/ascorbate sysem.
低密度脂蛋白（LDL）的氧化修饰被认为是动脉粥样硬化发生和发展的一个重要因素。抗氧化剂已被证明可保护LDL免受氧化，并在动物体内抑制动脉粥样硬化的发展。目前正在测试强效合成抗氧化剂，但它们对人类使用不一定安全。我们在此表征了IRFI005的抗氧化活性，IRFI005是Raxofelast（IRFI0016）的活性代谢产物，Raxofelast是一种正在临床开发的新型维生素E合成类似物，并证明它可防止LDL的氧化修饰。IFI005抑制了通过丙二醛生成、电泳迁移率和载脂蛋白B100荧光测量的LDL氧化修饰。在氧化过程中，IRF1005被消耗并形成苯醌氧化产物。IRFI005强大的抗氧化活性至少部分是由链断裂机制介导的，因为它是一种有效的过氧自由基清除剂，速率常数k（IRFI005 + LOO（o））为1.8×10（6）M（-1）s（-1）。4. IRFI005基本上保留了与LDL相关的抗氧化剂、α-生育酚和类胡萝卜素，并且当与生理水平的抗坏血酸共同孵育时，可协同抑制LDL氧化。IRFI005与Trolox共同孵育也产生了协同效应，并且在Trolox-苯醌氧化产物的形成中出现了延迟期。通过将IRFI005与掺入亚油酸胶束中的α-生育酚共同孵育，也证明了对脂质过氧化的协同抑制。这些数据强烈表明，IRFI005可以通过类似于维生素E/抗坏血酸系统的循环机制发挥作用。
