MECHANISMS OF CYTOPROTECTION BY HYDROPHILIC BILE SALTS

描述(取自应用程序) 胆盐与肝细胞的细胞膜和细胞膜相互作用， 肠上皮细胞和胆管上皮细胞。尽管人们越来越多地了解 胆汁的物理化学，关于胆盐的知之甚少 与膜脂的相互作用。胆盐就像一把双刃剑： 在胆汁淤积期间，胆盐积累，很可能是最终常见的 进一步的肝脏损害发生的途径；在结肠中胆盐起着 一种共同致癌物质。尽管某些亲水性胆盐，如 熊去氧胆酸盐结合物已被证明在 在细胞水平上对抗疏水性胆盐的细胞毒性效应 在未知的情况下发生这种情况的机制。 这项提议提出了胆汁的洗涤剂特性如何的基本问题 盐及其混合物改变细胞膜的屏障功能以 潜在的有毒物质，如钙，以及如何保护胰岛 亲水性胆盐似乎可以改善这些影响。在…的基础上 这里描述的初步数据，我们提出了两个假设：(1)单体 疏水性胆盐的水溶液浓度具有细胞毒性，因为它们 可以通过细胞膜快速运输二价阳离子， 不依赖于蛋白质通道；以及(2)细胞保护能力 亲水性胆盐不依赖于膜内相互作用，而是依赖于 同时含有疏水性和亲水性的简单胶束的形成 胆盐；因此，在物理化学基础上的细胞保护仅发生在 在存在简单胶束的情况下，如小管 薄膜。 这项提案的具体目标涉及两个问题：如何 疏水性胆盐对膜有毒性吗？亲水性胆盐是如何 作为细胞保护剂？通过比较生理成分 模型脂质系统与天然膜，我们将确定其重要性 胆盐介导的生理性细胞膜通透性增加 系统，并探索细胞保护的物理化学基础 肝小管膜和肝细胞内的水平。我们相信 阐明了混合物的物理化学机制 亲水和疏水的胆盐与膜相互作用将允许 了解胆盐的细胞毒性和细胞保护作用，以及 为其他药物的优化设计提供基础 治疗慢性胆汁淤积症。

DESCRIPTION (Taken from application) Bile salts interact with cell and organelle membranes in hepatocytes, enterocytes, and biliary epithelial cells. Despite growing knowledge of the physical chemistry of bile, far less is known regarding bile salt interactions with membrane lipids. Bile salts act as a double edged sword: during cholestasis bile salts accumulate and are most likely a final common pathway by which further liver damage occurs; in the colon bile salts act as a co-carcinogen. Although certain hydrophilic bile salts such as ursodeoxycholate conjugates have been demonstrated to protect at the cellular level against the cytotoxic effects of hydrophobic bile salts, the mechanism by which this occurs in unknown. This proposal asks fundamental question of how detergent properties of bile salts and their mixtures alter the barrier function of cell membranes to potentially toxic agents such as calcium, and how cyptoprotective hydrophilic bile salts appear to ameliorate these effects. On the basis of preliminary data described herein, we propose two hypotheses: (1) monomeric aqueous concentrations of hydrophobic bile salts are cytotoxic because they can rapidly transport divalent cations across cellular membranes, independent of protein channels; and (2) the cytoprotective ability of hydrophilic bile salts depends not on intramembrane interactions, but on formation of simple micelles containing both hydrophobic and hydrophilic bile salts; hence, cytoprotection on a physical chemical basis occurs solely under conditions where simple micelles are present such as the canalicular membrane. The specific aims of this proposal address two questions: How are hydrophobic bile salts toxic to membranes? How do hydrophilic bile salts act as cytoprotective agents? By comparison of physiologically composed model lipid systems with native membranes, we will determine the importance of bile salt-mediated increases in membrane permeability in physiological systems, and explore the physical-chemical basis of cytoprotection both at the level of the canalicular membrane and within the hepatocyte. We believe that elucidating physical-chemical mechanisms by which mixtures of hydrophilic and hydrophobic bile salts interact with membranes will allow an understanding of the cytotoxic and cytoprotective effects of bile salts, and provide a foundation for optimal design of other pharmacological agents to treat chronic cholestasis.