ROLE OF CYTOCHROME-P-450 IN REPERFUSION INJURY OF THE RABBIT LUNG
ROLE OF CYTOCHROME-P-450 IN REPERFUSION INJURY OF THE RABBIT LUNG
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DOI：
10.1172/jci114859
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发表时间：
1990-11-01
影响因子：
15.9
通讯作者：
HOIDAL, JR
中科院分区：
文献类型：
--
作者：
BYSANI, GK;KENNEDY, TP;HOIDAL, JR
活性氧是缺血组织再灌注损伤的主要原因。在再灌注过程中，活性氧需要铁等过渡金属来介导它们的主要毒性作用。黄嘌呤氧化酶是缺血再灌注损伤过程中活性氧的重要来源，但并非在所有器官或物种中都存在。由于细胞色素P-450酶是在基础条件下和高氧条件下产生超氧阴离子（O2-）的重要肺源，并为羟基自由基（. oh）的形成和脂质过氧化的传播提供必要的铁催化剂，我们假设细胞色素P-450可能在介导缺血再灌注损伤中具有潜在的作用。在本报告中，我们探讨了细胞色素P-450酶在兔肺再灌注损伤模型中的作用。P-450抑制剂8-甲氧基补骨脂素、胡椒酰丁醇和西咪替丁显著降低经血管液体通量引起的肺水肿。西咪替丁阻止再灌注相关的肺微血管通透性增加，这是通过125i -白蛋白从血管间隙进入肺水和肺泡液来测量的。P-450抑制剂也阻止了模型中硫代巴比妥酸反应产物肺组织水平的增加。通过肺灌注液中琥珀酰化铁细胞色素c的体内减少来测量，P-450抑制剂不能阻断缺血再灌注肺增强的O2生成，但确实阻止了再灌注后非蛋白质结合的低分子量铁螯合物的增加。因此，细胞色素P-450酶不太可能是增强氧生成的主要来源，但在再灌注期间介导兔肺氧化损伤时，它是铁的重要来源。这些结果表明细胞色素P-450在肺再灌注损伤中的重要作用，并为该疾病提供了潜在的新疗法。
Reactive oxygen species are a major cause of damage occurring in ischemic tissue after reperfusion. During reperfusion transitional metals such as iron are required for reactive oxygen species to mediate their major toxic effects. Xanthine oxidase is an important source of reactive oxygen species during ischemia-reperfusion injury, but not in all organs or species. Because cytochrome P-450 enzymes are an important pulmonary source of superoxide anion (O2-) generation under basal conditions and during hyperoxia, and provide iron catalysts necessary for hydroxyl radical (.OH) formation and propagation of lipid peroxidation, we postulated that cytochrome P-450 might have a potential role in mediating ischemia-reperfusion injury. In this report, we explored the role of cytochrome P-450 enzymes in a rabbit model of reperfusion lung injury. The P-450 inhibitors 8-methoxypsoralen, piperonyl butoxide, and cimetidine markedly decreased lung edema from transvascular fluid flux. Cimetidine prevented the reperfusion-related increase in lung microvascular permeability, as measured by movement of 125I-albumin from the vascular space into lung water and alveolar fluid. P-450 inhibitors also prevented the increase in lung tissue levels of thiobarbituric acid reactive products in the model. P-450 inhibitors did not block enhanced O2- generation by ischemic reperfused lungs, measured by in vivo reduction of succinylated ferricytochrome c in lung perfusate, but did prevent the increase in non-protein-bound low molecular weight chelates of iron after reperfusion. Thus, cytochrome P-450 enzymes are not likely a major source of enhanced O2- generation, but serve as an important source of iron in mediating oxidant injury to the rabbit lung during reperfusion. These results suggest an important role of cytochrome P-450 in reperfusion injury to the lung and suggest potential new therapies for the disorder.