SUPEROXIDE GENERATION FROM ENOS DEPENDENT REDOX CYCLING OF ADRIAMYCIN

阿霉素的 ENOS 依赖性氧化还原循环生成超氧化物

• 批准号: 6307850
• 负责人: BETTIE SUE SILER MASTERS
• 金额: $ 1.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6307850
• 关键词: bioengineering /biomedical engineering; biological products; biomaterials; biomedical resource; enzymes; proteins

The clinical use of the quinone-containing chemotherapeutic agent adriamycin is restricted by a severe dose-dependent cardiotoxicity. The mechanism underlying cytotoxicity has been linked to an increased generation of superoxide. The NAD(P)H-dependent enzymatic one-electron reduction of adriamycin generates the adriamycin semiquinone radical which undergoes redox-cycling in the presence of oxygen to generate superoxide and adriamycin. Thereby adriamycin provides a kinetic mechanism for one-electron reduction of oxygen by NAD(P)H. Here we show that endothelial nitric oxide synthase (eNOS) stimulates the generation of superoxide from adriamycin. Adriamycin binds to eNOS with a Km of approx. 5.0 micromole as determined from NADPH consumption and ESR spin-trapping of superoxide. Superoxide generation from eNOS/adriamycin is not dependent on the presence of CA(2+)/CaM and is abolished by the flavoprotein inhibitor dephenyleneiodonium. This strongly suggests that adriamycin undergoes reduction at the reductase domain of eNOS. One of the consequences of eNOS-mediated reductive activation of adriamycin is decreased production of nitric oxide and increased superoxide formation. This may lead eNOS to generate peroxynitrite, a potent oxidant implicated in several vascular pathologies.

含醌类化疗药物的临床应用 阿霉素受到严重的剂量依赖性心脏毒性的限制。 细胞毒性的潜在机制与增加的 生成超氧化物。 NAD（P）H依赖性酶 阿霉素的单电子还原产生阿霉素， 半醌自由基，其在存在下经历氧化还原循环， 氧气生成超氧化物和阿霉素。 因此阿霉素 提供了一个动力学机制，为单电子还原氧， NAD（P）H。 在这里，我们表明，内皮型一氧化氮合酶（eNOS） 刺激阿霉素产生超氧化物。 阿霉素 与eNOS结合的Km约为 5.0微摩尔，由 NADPH消耗和ESR自旋捕获超氧化物。 超氧 eNOS/阿霉素的产生不依赖于 CA（2+）/CaM，并被黄素蛋白抑制剂消除 去亚苯基碘鎓 这有力地表明阿霉素经历了 在eNOS的还原酶结构域的还原。 的后果之一 eNOS介导的阿霉素还原活化降低 产生一氧化氮和增加超氧化物的形成。 这 可能导致eNOS产生过氧亚硝酸盐，这是一种涉及 在几种血管病变中的作用