CHEMICAL TOXICITY AND VITAMIN E REGULATION

这项研究项目的长期目标是用完好的小鼠和 大鼠需要(1)阐明体内保护系统的机制 它们依赖于维生素E，(2)这些保护系统与 化学毒性的机制，包括氧化应激和 损害，以及(3)研究这些保护系统之间的相互作用 将完整的动物用于器官间的考虑。有针对性的L， 建议进行研究以阐明维生素E的作用机制。 在生理和病理条件下分泌到胆汁中， 包括化学改变的胆汁分泌。我们将确定 分泌到胆汁中的维生素E在多大程度上被重新吸收 无论是正常的还是病理的条件来检验这一假设 胆小管MDR2 P-糖蛋白在胆汁分泌中起重要作用 维生素E我们将使用最近开发的mdr2基因敲除小鼠，它 胆汁中缺乏磷脂，以探讨其关系 维生素E状态和磷脂稳态之间的关系。此外，AS 部分专门针对L我们将研究维生素E与 状态，以及胆汁中维生素E的分泌和GSH的动态平衡 最近利用γ-谷氨酰转肽酶(GGT)基因敲除小鼠 由贝勒大学迈克尔·利伯曼博士的实验室开发。 一项与亚利桑那大学Daniel Liebler博士的合作研究是 在特定目标2中提出，以研究体内摄入量和 维生素E的氧化产物我们的假设是 维生素E的产物谱随氧化机制的不同而不同 挑战和动物的GSH状态；某些氧化产物， 可以在血液中检测到的，可以作为 肝脏氧化应激的程度。这些实验预计将 更好地理解体内可能产生的“节制”效应 病理条件下谷胱甘肽和维生素E的含量。在具体目标3中，我们 将使用一种不能产生维生素C的Wistar大鼠 研究维生素E的周转和形成的氧化产物 在正常代谢和氧化应激条件下；我们将使用 同时提供3种水平的维生素E和维生素C的饮食 假设维生素C的状态会对营业额产生影响 维生素E的含量以及维生素E氧化的数量和种类 产品，当比较组织中维生素E含量低和高的动物时 在病理条件下的水平。

The long range objectives of this research project with intact mice and rats are to (1) elucidate the mechanisms of in vivo protective systems which are dependent on vitamin E, (2) relate these protective systems to mechanisms of chemically induced toxicity including oxidative stress and damage, and (3) investigate the interactions of these protective systems using intact animals for interorgan considerations. In Specific Aim l, studies are proposed to elucidate the mechanism by which vitamin E is secreted into the bile under both physiologic and pathologic conditions, including chemically altered bile secretion. We will determine the extent to which vitamin E secreted into the bile is reabsorbed under both normal and pathologic conditions to test the hypothesis that canalicular mdr2 P-glycoprotein is important in the biliary secretion of vitamin E. We will use the recently developed mdr2 knockout mice, which lack phospholipids in their bile, to investigate the relationship between vitamin E status and phospholipid homeostasis. In addition, as part of specific aim l we will study the relationship between vitamin E status, and the biliary secretion of vitamin E, and GSH homeostasis using the gamma-glutamyl transpeptidase (GGT) knockout mice recently developed in the laboratory of Dr. Michael Lieberman, Baylor University. A collaborative study with Dr. Daniel Liebler, University of Arizona, is proposed in Specific Aim 2 to investigate the in vivo consumption and oxidation products of vitamin E. Our hypothesis is that the oxidation product profile of vitamin E will vary with the mechanism of oxidative challenge and the GSH status of the animal; certain oxidation products, which can be detected in the blood, may serve as biomarkers of the extent of hepatic oxidative stress. These experiments are expected to provide a better understanding of the possible in vivo "sparing" effect of GSH and vitamin E under pathologic conditions. In Specific Aim 3 we will use a strain of Wistar rats which are unable to produce vitamin C to investigate the turnover of vitamin E and oxidation products formed under both normal metabolic and oxidative stress conditions; we will use diets which provide 3 levels of both vitamin E and vitamin C. Our hypothesis is that vitamin C status will have an effect on the turnover of vitamin E, as well as the quantity and species of vitamin E oxidation products, when comparing animals with low v.s. high tissue vitamin E levels under pathologic conditions.