AGING ON EFFLUX AND TURNOVER OF HEPATIC GLUTATHIONE

谷胱甘肽(GSH)是生物体内普遍存在的一种重要的三肽。 哺乳动物的有机体。它在解毒方面起着至关重要的作用 外源生物、亲电体、过氧物和氧自由基。关于 5%的细胞氧化代谢产生自由基形式的 氧气。有人提出，累积的，不可逆转的 这一过程对细胞结构/功能的破坏可能是 衰老的关键机制。因为GSH是细胞内的主要 防御剂对这一过程的动态平衡及其调控 在衰老的有机体中至关重要。的关键作用 肝脏是肝脏，肝外GSH代谢使其 谷胱甘肽代谢中最重要的器官。整体而言 这项建议的目的是勾勒出 肝组织谷胱甘肽周转和外流的变化机制 年龄的作用。特别是，将实现以下具体目标 追求：(1)确定肝脏动力学的变化 肝窦和管状GSH流出随年龄的变化。我们 将定义观察到的承运人中介的下降 随年龄增长的正弦流出是由于Vmax、Km或两者的变化。 我们还将准确地定义动力学上的变化 胆汁流出随年龄增长，通过阻断胆汁中谷胱甘肽的水解物 在-125。(二)环境变化机制的确定 肝GSH周转率随年龄的变化。使用改进的设计和 方法：测定小鼠肝脏GSH周转率、肝组织GSH周转率。 肝脏GSH及其与肝窦和胆汁流出的关系 将通过示踪动力学方法和 多室分析。(3)划定 肝脏GSH池大小对周转和外流的扰动。 这些研究将更深入地探讨 肝窦和小管外流的定量贡献 肝脏总周转率，并提供更严格的测试 肝脏GSH池的均质性。(4)确定 硫磺氨基酸可用性的作用。这些研究将 探讨与年龄相关的肝脏摄取 蛋氨酸和半胱氨酸。(5)发展动力， 大鼠肝脏GSH周转和外流的房室模型 衰老。我们的实验结果将由以下人员分析 多隔室方法，目的是将 谷胱甘肽周转和外流综合模型的研究结果 在衰老过程中。

Glutathione (GSH) is a ubiquitous and vital tripeptide in mammalian organisms. It plays a critical role in detoxification of xenobiotics, electrophiles, peroxides and oxygen radicals. About 5% of cellular oxidative metabolism produces radical forms of oxygen. It has been proposed that the cumulative, irreversible damange by this process to cellular structure/function could be a key mechanism of aging. since GSH is the major intracellular defense agent against this process, its homeostasis and regulation in the aging organism is of utmost importance. The key role of the liver is hepatic and extrahepatic GSH metabolism makes it the organ of prime importance in GSH metabolism. The overall purpose of this proposal is to delineate the characteristics and mechanisms of changes in turnover and efflux of hepatic GSH as a function of age. In particular the following specific aims will be pursued: (1) Identification of changes inthe kinetics of hepatic sinusoidal and canalicular GSH efflux as a function of age. We will define whether the observed decline in the carrier-mediated sinusoidal efflux with age is due to changes in Vmax; Km, or both. We will also accurately define the changes in the kinetics of biliary efflux with age, by blocking biliary hydrolysis of GSH using AT-125. (2) Determination of the mechanisms of changes in the heptatic GSH turnover with age. Using improved designs and methods, the turnover rate of hepatic GSH turnover rate of hepatic GSH and its relationship to sinusoidal and biliary efflux will be measured by tracer-kinetic methods and multicompartmental analysis. (3) Delineation of the effect of perturbation of hepatic GSH pool size on turnover and efflux. These studies will probe in more depth the relationships and quantitative contribution of sinusoidal and canalicular efflux to the total hepatic turnover and provide more rigorous testing of the homogeneity of the hepatic GSH pool. (4) Determination of the role of availability of sulfur amino acids. These studies will explore the age-related correlates of hepatic uptake of methionine and cysteine. (5) Development of kinetic, compartmental model of hepatic GSH turnover and efflux in aging. The results of our experiments will be analyzed by multicompartmental methods with the aim of integrating the findings into a comprehensive model of GSH turnover and efflux in aging.