Nitroxides as Protectors Against Oxidative Stress

氮氧化物作为氧化应激的保护剂

• 批准号: 6558332
• 负责人: JAMES B MITCHELL
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6558332
• 关键词: Rodentias; analog; antioxidants; cytotoxicity; drug screening /evaluation; electron spin resonance spectroscopy; estrogens; free radical scavengers; gene targeting; genetically modified animals; glucose 6 phosphatase; glutathione; ionizing radiation; laboratory mouse; longevity; neoplastic cell; nitrogen oxides; oxidation reduction reaction; oxidative stress; oxidizing agents; piperidine; radiation protection; radioprotective agents; superoxide dismutase; tissue /cell culture

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 a tumor-bearing animal model has shown more rapid reduction of nitroxides in tumor compared to normal tissue. Recent studies have shown that cells deficient in glucose 6 phosphate dehydrogenase (G6PD) reduce the nitroxide to the hydroxylamine much slower than control cells suggesting a role for this important biochemical pathway in nitroxide reduction. We have also recently shown that intracellular glutathione levels are a major determinant of nitroxide reduction in tissues. These studies will enable us to best determine the appropriate routes of administration for nitroxides as potentially selective radioprotectors of normal tissues. We have also recently shown that nitroxides protect against the cytotoxicity and mutagenicity of estrogen metabolites. These studies will be expanded to explore their impact to in vivo tumor models. Lastly, preliminary studies have indicated that long-term administration of tempol (in the food or drinking water) to p53 knockout mice extends their life span. Additionally in control mice we have observed that long-term administration of tempol results in dramatic weight reduction, which we have recently correlated, with increased expression of mitochondrial uncoupling protein 2 in skeletal muscle. Since nitroxides readily penetrate cell membranes and are potent antioxidants, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies, prevention of cataracts, inflammatory processes, and aging.

已被用作 EPR 自旋标记的氮氧化物（例如 tempol）已被证明具有超氧化物歧化酶 (SOD) 活性，并且是保护细胞免受多种氧化应激（包括过氧化氢、超氧化物、有机氢过氧化物、氧化还原循环化疗药物和电离辐射）的非常有效的试剂。我们已经证明 Tempol 可以保护体外细胞和小鼠免受电离辐射。因此，硝基氧代表了一类新型辐射防护剂，可广泛用于保护人类免受辐射。重要的是，我们已经证明 tempol 不能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。对荷瘤动物模型进行的体内电子顺磁共振成像研究表明，与正常组织相比，肿瘤中的氮氧化物减少得更快。最近的研究表明，缺乏葡萄糖 6 磷酸脱氢酶 (G6PD) 的细胞将硝基氧还原为羟胺的速度比对照细胞慢得多，这表明这一重要的生化途径在硝基氧还原中发挥着作用。我们最近还表明，细胞内谷胱甘肽水平是组织中氮氧化物减少的主要决定因素。这些研究将使我们能够最好地确定硝基氧作为正常组织的潜在选择性放射保护剂的适当给药途径。我们最近还表明，硝基氧可以防止雌激素代谢物的细胞毒性和致突变性。这些研究将得到扩展，以探索它们对体内肿瘤模型的影响。最后，初步研究表明，长期给予 p53 基因敲除小鼠 tempol（在食物或饮用水中）可延长其寿命。此外，在对照小鼠中，我们观察到长期服用 tempol 会导致体重显着减轻，我们最近将其与骨骼肌中线粒体解偶联蛋白 2 表达增加相关联。由于硝基氧很容易穿透细胞膜并且是有效的抗氧化剂，因此它们可用于其他医学研究领域，例如缺血/再灌注损伤研究、预防白内障、炎症过程和衰老。