Chevion M
Department of Cellular Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Free Radic Res Commun. 1991;12-13 Pt 2:691-6. doi: 10.3109/10715769109145848.
Free radicals have been incriminated in a variety of injurious processes including the toxicity of the herbicide paraquat and the damage following ischemia and reperfusion of different organs. Based on the assumption that iron and copper could serve as mediators for the transformation of relatively low reactive species (such as superoxide radicals, hydrogen peroxide, ascorbate, and others) to the highly reactive species, in the site-specific metal-mediated mechanism, two new modes for intervention have been tried out. The first is the introduction of specific chelators that "pull" out redox-active and available metals, and by this reduce the apparent damage. Desferrioxamine was shown to protect bacterial cells and mammals against the poisonous effects of paraquat. Using the retrogradly perfused isolated rat heart, we have demonstrated that the chelator neocuproine, which effectively binds both iron and copper provides a major protection against hydrogen peroxide-induced cardiac damage and against ischemia/reperfusion-induced arrhythmias. Likewise, TPEN a heavy metal chelator, provides almost total (greater than 90%) protection against ischemia/reperfusion-induced arrhythmias. The other mode of intervention is the use of redox-inactive metal ions that could compete for the binding sites of iron and copper, and by this "push" these metal ions out, lead to their displacement, and divert the site of free radical attack. Applying Zn(II) complexes provided a marked protection against metal mediated free radical-induced damage in the copper-mediated paraquat toxicity to E. coli, and in the arrhythmias induced by ischemia and reperfusion. It is proposed that the complex zinc-desferrioxamine would be the ultimate protector being effective by both the "pull" and "push" mechanisms.
自由基已被认为与多种损伤过程有关，包括除草剂百草枯的毒性以及不同器官缺血再灌注后的损伤。基于铁和铜可作为相对低反应性物种（如超氧自由基、过氧化氢、抗坏血酸等）转化为高反应性物种的介质这一假设，在位点特异性金属介导机制中，人们尝试了两种新的干预模式。第一种是引入特定的螯合剂，将具有氧化还原活性且可利用的金属“螯合”出来，从而减少明显的损伤。去铁胺已被证明可保护细菌细胞和哺乳动物免受百草枯的毒害作用。利用逆行灌注的离体大鼠心脏，我们已证明能有效结合铁和铜的螯合剂新铜试剂可对过氧化氢诱导的心脏损伤以及缺血/再灌注诱导的心律失常提供主要保护。同样，重金属螯合剂三（2-吡啶甲基）胺几乎能完全（大于90%）保护心脏免受缺血/再灌注诱导的心律失常。另一种干预模式是使用无氧化还原活性的金属离子，这些离子可竞争铁和铜的结合位点，从而将这些金属离子“挤出”，导致它们被取代，并转移自由基攻击的位点。应用锌（II）配合物可显著保护细胞免受金属介导的自由基诱导的损伤，如在铜介导的百草枯对大肠杆菌的毒性作用以及缺血再灌注诱导的心律失常中。有人提出锌-去铁胺配合物将是最终的保护剂，通过“螯合”和“挤出”机制发挥作用。
