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: 3941594
• 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/3941594
• 关键词: active transport; aminoacid transport; apical membrane; basolateral membrane; egg /ovum; environmental toxicology; epithelium; glutarates; insulin; ionophores; membrane permeability; nonelectrolyte transport; p aminohippurate; toxin metabolism

The ability to transport solutes across epithelial membranes is a vital function of many organs, e.g., kidney. 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. Recent work has focused on the renal organic anion transport system, since this system determines the extent of elimination of toxic xenobiotics. Using p-aminohippuric acid (PAH), a model substrate for this system, it was shown that transport requires the coordinated action of two distinct carrier proteins. One mediates exchange of external PAH for internal glutaric acid (or alpha-ketoglutarate). The second taps energy stored in the Na gradient to drive glutarate back into the cell, maintaining the steep (in greater than out) glutarate gradient needed to drive PAH uptake. Together the two systems indirectly couple BLM PAH transport to the sodium gradient and metabolic energy stores. BBM are unable to couple the two processes. Thus, PAH secretion requires BLM uptake and intracellular accumulation, followed by exit of PAH down its electrochemical gradient at the BBM. Studies using electrophysiological and radiochemical techniques to examine organic cation transport (the second major xenobiotic excretory pathway) show that the basolateral step in secretion of the model organic cation, tetraethylammonium (TEA), is carrier-mediated and strongly potential dependent. To focus on intracellular events, including binding, subcellular compartmentalization, and information transfer between the surface membrane and intracellular organelles, cryomicrodissection and microinjection techniques were developed in amphibian oocytes. Particularly striking was the observation that intracellular insulin, at doses (0.5-5 pmoles) too low to alter surface membrane transport, caused marked changes in both protein and RNA synthesis rates. These preliminary results argue strongly for a physiological role of intracellular insulin receptors.

跨上皮膜运输溶质的能力是 许多器官，例如肾脏的重要功能。 反过来，上皮 运输取决于位于 顶端（BBM）和基底外侧（BLM）膜。 因为他们 复杂的组织，功能重要性和暴露 位置，上皮膜特别容易受到 外国化学物质的有毒作用。 最近的工作重点是 肾脏有机阴离子传输系统，因为该系统 确定消除有毒异种生物的程度。 使用 p-氨基硫酸（PAH），该系统的模型底物，它 表明运输需要两个协调的动作 不同的载体蛋白。 一个人调节外部PAH的交换 用于内部谷氨酸（或α-酮戊二酸）。 第二个 利用存储在NA梯度中的能量，将谷氨酸驱动回到 细胞保持陡峭（大于外的）谷氨酸 驱动PAH摄取所需的梯度。 在一起两个系统 间接夫妇BLM PAH运输到钠梯度和 代谢能量存储。 BBM无法搭配两个 过程。 因此，PAH分泌需要BLM吸收和 细胞内积累，然后退出PAH BBM的电化学梯度。 使用的研究 电生理和放射化学技术检查 有机阳离子运输（第二个主要的异源生物排泄物 途径）表明模型分泌的基底外侧步骤 有机阳离子，四乙基铵（TEA），是载体介导的 并具有强大的依赖性。 专注于细胞内 事件，包括结合，亚细胞隔室化和 表面膜之间的信息传递 细胞内细胞器，冷冻分解和显微注射 技术是在两栖动物卵母细胞中开发的。 特别 引人注目的观察到细胞内胰岛素的剂量 （0.5-5 pmoles）太低而无法改变表面膜传输， 引起蛋白质和RNA合成速率的明显变化。 这些初步结果强烈主张生理角色 细胞内胰岛素受体。