CHEMICAL TOXICITY AND VITAMIN E REGULATION

本研究项目的长期目标是使用完整的小鼠， 大鼠的目的是（1）阐明体内保护系统的机制 依赖于维生素E，（2）将这些保护系统与 化学诱导的毒性机制，包括氧化应激和 （3）研究这些保护系统的相互作用 使用完整的动物进行器官间的考虑。在具体目标1中， 建议进行研究以阐明维生素E 在生理和病理条件下分泌到胆汁中， 包括胆汁分泌的化学改变康贝特人将以 分泌到胆汁中的维生素E被重吸收的程度 在正常和病理条件下测试假设， 小管mdr 2 P-糖蛋白在胆汁分泌中是重要的， 维生素E.我们将使用最近开发的mdr 2基因敲除小鼠， 胆汁中缺乏磷脂， 维生素E状态和磷脂稳态之间的关系另外作为 部分具体目标l我们将研究维生素E 维生素E的胆汁分泌和GSH稳态 最近使用γ-谷氨酰转肽酶（GGT）基因敲除小鼠， 在贝勒大学的迈克尔·利伯曼博士的实验室里开发的。 与亚利桑那大学的丹尼尔利布勒博士的一项合作研究是 在具体目标2中提出研究体内消耗， 维生素E的氧化产物。我们的假设是 维生素E的产品概况将随着氧化机制而变化。 激发和动物的GSH状态;某些氧化产物， 其可以在血液中检测到，可以作为 肝脏氧化应激程度。这些实验预计将 更好地理解可能的体内“节省”效应 GSH和维生素E的水平。具体目标3 将使用一种不能产生维生素C的Wistar大鼠 研究维生素E和氧化产物形成的周转率 在正常代谢和氧化应激条件下，我们将使用 饮食提供3个水平的维生素E和维生素C。我们 假设是维生素C的状态会影响营业额 以及维生素E氧化的数量和种类 产品，当比较动物与低v.s.高组织维生素E 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.