DETOXIFICATION AND TOXICITY OF HYDROXYALKENALS IN HEART

羟基烯醛在心脏中的解毒和毒性

• 批准号: 6183944
• 负责人: Aruni Bhatnagar
• 金额: $ 22.52万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 2001-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6183944
• 关键词: adenosine triphosphate; aldehyde reductase; aldehydes; detoxification; enzyme activity; glutathione; heart metabolism; heart pharmacology; high performance liquid chromatography; human tissue; laboratory rat; muscle cells; oxidative stress; oxidoreductase inhibitor; reperfusion; toxicology; voltage /patch clamp

The long-term goal of this project is to understand the mechanism by which 4-hydroxyalkenals and related aldehydes are detoxified by the heart and to assess their contribution to myocardial oxidative injury. These aldehydes are generated by endogenous lipid peroxidation during metabolism of anticarcinogens, food products and industrial and environmental pollutants. However, the cardiac metabolism of these aldehydes and their contribution to free radical injury are not well understood. Our hypothesis is that aldose reductase-catalyzed reduction constitutes the major pathway for the detoxification of these aldehydes in the heart. In association with glutathione conjugation, this pathway minimizes oxidative injury by promoting the detoxification of unsaturated aldehydes. The aim of the proposed studies is to understand the role of aldose reductase in detoxifying unsaturated aldehydes and to identify the contribution of this detoxification pathway to cardiac antioxidant defenses. For these studies, aldose reductase will be purified to homogeneity from human heart and its catalytic efficacy in reducing hydroxyalkenals, related aldehydes and their glutathione adducts will be examined. For most metabolic studies 4-hydroxy-2-trans nonenal (HNE) will be used as a model unsaturated aldehyde. We will identify the major cellular metabolites of HNE isolated rat ventricular myocytes and assess the relative contribution of aldose reductase to HNE metabolism. In order to examine the efficiency of this enzyme in promoting HNE metabolism and minimizing its toxicity, the effects of inhibiting aldose reductase on HNE-induced myocyte hypercontracture and ATP depletion will be studied. During whole-cell patch-clamp, myocytes will be supplemented with aldose reductase to assess the role of this enzyme in attenuating the effects of HNE. In order to assess the, significance of aldose reductase- catalyzed reduction of HNE to cardiac oxidative injury we will examine the effects of aldose reductase inhibitors on the reperfusion injury to isolated perfused rat hearts. These studies will provide insights into the metabolic processes by which the heart detoxifies reactive aldehydes and help in understanding the role of these aldehydes as mediators of oxidative injury.

该项目的长期目标是通过以下方式了解该机制： 哪些 4-羟基烯醛和相关醛类被心脏解毒 并评估它们对心肌氧化损伤的贡献。这些 醛类是由内源性脂质过氧化作用产生的 抗癌剂、食品和工业品的代谢 环境污染物。然而，这些物质的心脏代谢 醛类及其对自由基损伤的贡献尚不清楚 明白了。我们的假设是醛糖还原酶催化还原 构成这些醛解毒的主要途径 在心里。与谷胱甘肽缀合相关，该途径 通过促进不饱和物质的解毒来最大限度地减少氧化损伤 醛类。拟议研究的目的是了解 醛糖还原酶在解毒不饱和醛中的作用并鉴定 这种解毒途径对心脏抗氧化的贡献 防御。对于这些研究，醛糖还原酶将被纯化为 来自人类心脏的同质性及其减少的催化功效 羟基烯醛、相关醛及其谷胱甘肽加合物将 检查了。对于大多数代谢研究，4-羟基-2-反式壬烯醛 (HNE) 将 用作不饱和醛的模型。我们将确定主要 HNE分离大鼠心室肌细胞的细胞代谢并评估 醛糖还原酶对 HNE 代谢的相对贡献。为了 检查该酶促进 HNE 代谢的效率， 最大限度地减少其毒性，抑制醛糖还原酶的作用 将研究 HNE 诱导的心肌细胞过度挛缩和 ATP 耗竭。 在全细胞膜片钳过程中，肌细胞将补充醛糖 还原酶以评估该酶在减弱影响方面的作用 的 HNE。 为了评估醛糖还原酶的重要性- 我们将研究 HNE 催化减少心脏氧化损伤 醛糖还原酶抑制剂对大鼠再灌注损伤的影响 分离的灌注大鼠心脏。这些研究将提供见解 心脏解毒活性醛的代谢过程 并有助于理解这些醛作为介质的作用 氧化损伤。