Comparison of Clinically Used and Experimental Iron Chelators for Protection against Oxidative Stress-Induced Cellular Injury
Comparison of Clinically Used and Experimental Iron Chelators for Protection against Oxidative Stress-Induced Cellular Injury
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DOI：
10.1021/tx100125t
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发表时间：
2010-06-01
影响因子：
4.1
通讯作者：
Simunek, Tomas
中科院分区：
文献类型：
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作者：
Bendova, Petra;Mackova, Eliska;Simunek, Tomas
铁失衡在与多种病理状态相关的氧化应激中起着重要作用。因此，铁螯合可能是一种有效的治疗方法，但由于缺乏有效的配体，这一领域的进展受到阻碍。此外，螯合剂对氧化损伤的潜在有利作用必须与其自身因铁耗竭而产生的毒性和产生氧化还原活性铁络合物的能力进行权衡。在这项研究中，我们比较了选定的铁络合剂(临床上使用的药物和实验试剂)在保护细胞免受叔丁基氢过氧化氢(t-BHP)诱导的模型氧化损伤方面的有效性。此外，还测定了螯合剂及其铁络合物的细胞内螯合效率、氧化还原活性和细胞毒性。乙二胺四乙酸不能保护细胞免受t-BHP的细胞毒性，这显然是由于形成的铁络合物的氧化还原活性所致。亲水性去铁胺有一定的保护作用，但只有在很高的临床无法达到的浓度时才能发挥保护作用。更小和更亲油的螯合剂，去铁酮，去铁酮和吡哆醛异烟酰肼，在防止细胞氧化损伤方面明显更有效。就进入细胞内不稳定铁库而言，最有效的螯合剂是二-2-吡啶酮4，4-二甲基-3-氨基硫脲。然而，总体而言，在保护t-BHP的效率和螯合剂本身固有的细胞毒性方面，观察到最有利的性能是水杨醛异烟酰肼。这可能与后一种试剂的最佳亲脂性以及它产生不会引起显着氧化还原活性的铁络合物的能力有关。
Iron imbalance plays an important role in oxidative stress associated with numerous pathological conditions. Therefore, iron chelation may be an effective therapeutic approach, but progress in this area is hindered by the lack of effective ligands. Also, the potential favorable effects of chelators against oxidative injury have to be balanced against their own toxicity due to iron depletion and the ability to generate redox-active iron complexes. In this study, we compared selected iron chelators (both drugs used in clinical practice as well as experimental agents) for their efficacy to protect cells against model oxidative injury induced by tert-butyl hydroperoxide (t-BHP). In addition, intracellular chelation efficiency, redox activity, and the cytotoxicity of the chelators and their iron complexes were assayed. Ethylenediaminetetraacetic acid failed to protect cells against t-BHP cytotoxicity, apparently due to the redox activity of the formed iron complex. Hydrophilic desferrioxamine exerted some protection but only at very high clinically unachievable concentrations. The smaller and more lipophilic chelators, deferiprone, deferasirox, and pyridoxal isonicotinoyl hydrazone, were markedly more effective at preventing oxidative injury of cells. The most effective chelator in terms of access to the intracellular labile iron pool was di-2-pyridylketone 4,4-dimethy1-3-thiosemicarbazone. However, overall, the most favorable properties in terms of protective efficiency against t-BHP and the chelator's own inherent cytotoxicity were observed with salicylaldehyde isonicotinoyl hydrazone. This probably relates to the optimal lipophilicity of this latter agent and its ability to generate iron complexes that do not induce marked redox activity.