Nepomuceno M F, de Oliveira Mamede M E, Vaz de Macedo D, Alves A A, Pereira-da-Silva L, Tabak M
Departamento de Bioquímica, Instituto de Biologia, Universidade Estadual de Campinas, 13083-970, Campinas SP, Brazil.
Biochim Biophys Acta. 1999 May 12;1418(2):285-94. doi: 10.1016/s0005-2736(99)00038-3.
Dipyridamole (DIP), a coronary vasodilator, presents coactivator activity for a number of antitumor drugs as well as antioxidant activity in membrane systems. DIP and derivatives interact with membrane systems such as micelles, phospholipid monolayers and vesicles. The antioxidant effect of DIP and several derivatives upon iron-induced lipoperoxidation on mitochondria has been reported and a good correlation between the hydrophobicity and their protective effect was found (M.F. Nepomuceno et al., Free Radic. Biol. Med., 23 (1997) 1046-1054). In the present work an effort is made to better understand the role of DIP as inhibitor of Fe2+-induced lipid peroxidation in mitochondria. At low concentration, no significant effect on either state IV or state III respiration was found, discarding a possible direct interaction of DIP or RA-25 with the peripheral benzodiazepine receptor. The association constants for DIP and RA-25 in mitochondria were estimated, being 0.7 (mg/ml)-1 for DIP and 0.2 (mg/ml)-1 for RA-25. Oxygen consumption studies in the presence of FeSO4 showed that the antioxidant effect of DIP or RA-25 did not involved the initial step of Fe2+ oxidation. Our data strongly support the hypothesis that the antioxidant effect of both DIP and RA-25 is related to their partition in the lipid phase of the mitochondrial membrane and not to a specific interaction with membrane proteins. This protection may be due either to a direct inhibition of the propagation steps or a scavenger effect on the radicular species that would trigger the peroxidative process.
双嘧达莫（DIP）是一种冠状动脉血管扩张剂，对多种抗肿瘤药物具有共激活剂活性，在膜系统中也具有抗氧化活性。DIP及其衍生物可与胶束、磷脂单层和囊泡等膜系统相互作用。已有报道称DIP及其几种衍生物对铁诱导的线粒体脂质过氧化具有抗氧化作用，且发现其疏水性与其保护作用之间存在良好的相关性（M.F. Nepomuceno等人，《自由基生物学与医学》，23 (1997) 1046 - 1054）。在本研究中，我们致力于更好地理解DIP作为线粒体中Fe2 +诱导脂质过氧化抑制剂的作用。在低浓度下，未发现对状态IV或状态III呼吸有显著影响，排除了DIP或RA - 25与外周苯二氮䓬受体可能存在的直接相互作用。估算了DIP和RA - 25在线粒体中的缔合常数，DIP为0.7 (mg/ml)-1，RA - 25为0.2 (mg/ml)-1。在FeSO4存在下的耗氧研究表明，DIP或RA - 25的抗氧化作用不涉及Fe2 +氧化的初始步骤。我们的数据有力地支持了这样一种假设，即DIP和RA - 25的抗氧化作用与其在线粒体膜脂质相中的分配有关，而不是与膜蛋白的特异性相互作用。这种保护作用可能是由于直接抑制了传播步骤，或者是对引发过氧化过程的自由基物种具有清除作用。
