ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

膜功能改变在异生物毒性中的作用

• 批准号: 3918754
• 负责人: J B PRITCHARD
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3918754
• 关键词: active transport; aminoacid transport; apical membrane; basolateral membrane; biological information processing; egg /ovum; environmental toxicology; epithelium; glutarates; hormone regulation /control mechanism; insulin; ionophores; membrane channels; membrane permeability; membrane potentials; nonelectrolyte transport; toxin metabolism

The ability to transport solutes across epithelial membranes is a vital function of many organs, e.g., kidney, choroid plexus, gut. In turn, epithelial transport depends upon individual transport systems located in apical (BBM) and basolateral (BLM) membranes. Because of their complex organization, functional importance, and exposed location, epithelial membranes are particularly susceptible to toxic effects of foreign chemicals. Major recent emphasis has focused on the renal organic anion (OA) transport system, which determines the extent of elimination of many toxic xenobiotics. Isolated membrane vesicle studies demonstrate that OA transport is driven by indirect coupling to the Na gradient. An anion exchanger mediates exchange of external OA for internal glutaric acid (or a- ketoglutarate) and a second carrier taps energy stored in the Na gradient to drive glutarate back into the cell, maintaining the steep (in>out) glutarate gradient needed to drive OA uptake. Thus, BLM uptake leads to intracellular accumulation. Intracellular OA then exits across the BBM via another anion exchanger, producing net tubular secretion. Recent whole tissue studies not only confirm the importance of this system in rat kidney, but also demonstrate its contribution to OA transport in the kidneys of several other species and in other tissues, including the choroid plexus Similar studies utilizing both electrophysiological and radiochemical techniques to examine the organic cagtion (OC) transport system, show that the basolateral step in OC secretion is carrier-mediated and derives its primary driving force from the membrane potential. Membranes also play important roles in information transfer between the cell and its environment. Amphibian oocytes were used to examine the nature of insulin in action. These studies demonstrate that insulin, at physiological doses, acts directly on both membrane and intracellular sites to alter protein and RNA synthesis. Effects of intracellular and extracellular insulin were additive, suggesting separate modes of action.

跨上皮膜运输溶质的能力是 许多器官的重要功能，例如肾脏，脉络丛，肠道。 反过来，上皮运输取决于个人运输 位于顶端（BBM）和基底外侧（BLM）膜中的系统。 由于其复杂的组织，功能重要性以及 暴露的位置，上皮膜特别易感 外国化学物质的有毒作用。 最近重点的重点 专注于肾脏有机阴离子（OA）运输系统，该系统 确定消除许多有毒异种生物的程度。 分离的膜囊泡研究表明，OA的运输是 由间接耦合到NA梯度的驱动。 一个阴离子交换器 介导外OA交换内谷氨酸（或A- Ketoglutarate）和第二个载体点击Na中存储的能量 梯度将麸质驱动回细胞，保持 浸入OA吸收需要的陡峭（IN> OUT）麸质梯度。 因此， BLM摄取导致细胞内积累。 细胞内OA 然后通过另一个阴离子交换器在BBM上退出，产生 净管状分泌。 最近的整个组织研究不仅 确认该系统在Rat肾脏中的重要性，还确认 展示其对肾脏中OA运输的贡献 其他几种物种和其他组织，包括脉络膜 plexus使用电生理和 放射化学技术检查有机盒（OC） 运输系统，表明OC分泌的基底外侧步骤 是载体介导的，并从 膜电位。 膜在 细胞及其环境之间的信息传输。 两栖卵母细胞用于检查胰岛素的性质 行动。 这些研究表明，胰岛素，生理 剂量，直接作用于膜和细胞内部位 改变蛋白质和RNA合成。 细胞内和 细胞外胰岛素是加性的，暗示了单独的模式 行动。