THE PHARMACOLOGY OF INHIBITORS OF HEME PROTEIN-CATALYZED LIPID PEROXIDATION

血红素蛋白催化脂质过氧化抑制剂的药理学

• 批准号: 7209628
• 负责人: JOHN Alexander OATES
• 金额: $ 23.48万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7209628
• 关键词: acetaminophen; angiography; eicosanoid metabolism; eicosanoids; hemoprotein; human subject; inhibitor /antagonist; lipids; mass spectrometry; patient oriented research; peroxidation; pharmacology; statistics /biometry; subarachnoid hemorrhage; toxicology; vasospasm

Hemoprotein- catalyzed lipid peroxidation contributes to the pathophysiology of diseases in which myoglobin and hemoglobin are released from the antioxidant environment of cells. These include a major contribution of myoglobin-catalyzed lipid peroxidation to the renal failure produced by rhabdomyolysis and to microvascular constriction in myocardial ischemia. Lipid peroxidation induced by hemoglobin is correlated with the pathophysiology of subarachnoid hemorrhage, Falciparum malaria and sickle cell disease. Among the products of lipid peroxidation are the F2 -isoprostanes, which are highly potent vasoconstrictors. We have demonstrated that lipid peroxidation catalyzed by the peroxidase-like function of oxidized hemoproteins is inhibited by acetaminophen. In a rat model of rhabdomyolysis in which F2-isoprostanes generated intrarenally contribute to the renal failure, acetaminophen significantly reduced lipid peroxidation and markedly decreased the extent of renal failure. These findings provide a rationale for development of even more potent inhibitors. Compounds with lower ionization potential and bond dissociation enthalpy have been synthesized and found to have markedly increased potency as reductants of the ferryloxo radical of myoglobin and hemoglobin. Further testing of these compounds and synthesis of newer compounds in the series is proposed. The hypothesis that optimal inhibition of lipid peroxidation can be achieved by a combination of water soluble antioxidants that inhibit the radical initiator together with lipid soluble antioxidants that are chain breaking will be examined. The effect of acetaminophen will be evaluated in subarachnoid hemorrhage, in which evidence of lipid peroxidation correlates with time of delayed vasospasm and with severity of neurological deficits. This will be a pilot study in which acetaminophen based regimens will be tested for their ability to reduce lipid peroxidation assessed by measurement of F2 isoprostane levels in cerebrospinal fluid. Secondary endpoints will include vasospasm and brain ischemia as determined by magnetic resonance arteriography and imaging, as well as assessment of neurological outcome. The results could provide a basis for a larger outcome study, and a rationale for development of even more potent regimens for inhibiting hemoprotein-catalyzed lipid peroxidation in subarachnoid hemorrhage as well as in other diseases.

血蛋白 - 催化的脂质过氧化有助于肌红蛋白的病理生理学 血红蛋白从细胞的抗氧化剂环境中释放出来。这些包括主要贡献 肌红蛋白催化的脂质过氧化对横纹肌溶解产生的肾衰竭和 心肌缺血中的微血管收缩。血红蛋白诱导的脂质过氧化是相关的 蛛网膜下腔出血，恶性疟疾和镰状细胞病的病理生理学。之中 脂质过氧化的产物是F2-异丙烷，它们是高效的血管收缩剂。我们 已经证明脂质过氧化由氧化血蛋白的过氧化物酶样功能催化 对乙酰氨基酚抑制。在横纹肌溶解的大鼠模型中，其中F2-异前列腺产生了 内部有助于肾衰竭，对乙酰氨基酚显着降低脂质过氧化和 明显减少了肾衰竭的程度。这些发现为发展的基本原理提供了理由 更有效的抑制剂。电离电位较低和键解离焓的化合物已是 合成并发现作为效力的效力显着提高，因为 肌红蛋白和血红蛋白。进一步测试这些化合物并合成较新化合物 提出了系列。可以通过A来实现最佳脂质过氧化抑制的假说 水溶性抗氧化剂的组合，抑制自由基引发剂与脂质可溶性 将检查链断裂的抗氧化剂。对乙酰氨基酚的影响将在 亚蛛网膜下腔出血，其中脂质过氧化的证据与血管痉挛的时间相关 以及神经系统缺陷的严重程度。这将是一项试点研究，基于对乙酰氨基酚的方案 将测试其通过测量F2降低脂质过氧化评估的脂质过氧化的能力 在脑脊液中。次要终点将包括血管痉挛和脑缺血，确定 磁共振动脉造影和成像，以及神经系统结果的评估。结果 可以为更大的结果研究提供基础，以及开发更有效的基本原理 抑制蛛网膜下腔出血中抑制血蛋白催化脂质过氧化的方案 其他疾病。