NITROXIDES AS PROTECTORS AGAINST OXIDATIVE STRESS

已被用作EPR自旋标记的氮氧化物(如坦波尔)具有 已显示出超氧化物歧化酶(SOD)活性，并相当 保护细胞免受多种氧化损伤的有效物质 应激包括过氧化氢、超氧化物、有机过氧化氢、 氧化还原循环化疗药物和电离辐射。我们有 证明Tempoll对体外培养的细胞和小鼠均有保护作用 电离辐射。因此，氮氧化物代表了一类新的 可能在保护人类方面具有广泛用途的辐射保护器 抵御辐射。重要的是，我们已经证明了tempol不会 保护啮齿动物肿瘤组织；我们认为其机制涉及 正常组织与肿瘤组织的不同代谢还原特性。 荷瘤动物体内电子顺磁共振成像研究 动物们正在进行研究，以确定是否存在差异减少的 氮氧化物存在于正常组织和肿瘤组织之间。我们已经完成了一个 体外实验确定保护效果最好的氮氧化物 目的。超过110个氮氧化物在一个结构活性中被评价。 关系研究。我们已经确定了6种氮氧化物 比坦波尔(第一个氮氧化物)具有更强的辐射防护能力 具有辐射防护性能)，还鉴定了3个类似物 使有氧细胞变得对辐射敏感。将对这些代理进行评估并 与体内的坦波尔进行比较。我们最近发现，血红素蛋白 暴露在氧化剂下会形成剧毒的铁基部分和氮氧化物 使这些有毒物种解毒，并赋予增强的过氧化氢酶样活性 亚铁血红素种类。由于这些试剂很容易穿透细胞膜，所以它们 可用于医学研究的其他领域，如 缺血/再灌注损伤研究，预防白内障，炎症 过程和老化。

Nitroxides (such as tempol) which have been used as EPR spin labels have been shown to exhibit superoxide dismutase (SOD) activity and are quite effective agents in protecting cells against a wide variety of oxidative stresses including hydrogen peroxide, superoxide, organic hydroperoxides, redox-cycling chemotherapy drugs, and ionizing radiation. We have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Importantly, we have shown that tempol does not protect rodent tumor tissue; the mechanism of which we believe involves differential metabolic reduction properties of normal versus tumor tissue. In vivo electron paramagnetic resonance imaging studies in tumor-bearing animals are underway to determine if a differential reduction of nitroxides exists between normal and tumor tissue. We have completed an in vitro study to identify the most efficient nitroxide for protection purposes. Over 110 nitroxides were evaluated in a structure activity relationship study. We have identified 6 nitroxides that afford significantly more radioprotection than tempol (the first nitroxide shown to have radioprotective properties) and have also identified 3 analogs that radiosensitize aerobic cells. These agents will be evaluated and compared with tempol in vivo. We have recently shown that heme proteins exposed to oxidants form highly toxic ferryl moieties and that nitroxides detoxify these toxic species and confer enhanced catalase-like activity to heme species. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes and aging.