ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

跨上皮膜运输溶质的能力是一种 许多器官的重要功能，例如肾脏。反过来，上皮性 交通依赖于位于 顶膜(BBM)和基侧膜(BLM)。因为他们的 组织复杂，功能重要，并暴露出来 位置，上皮膜特别容易感染 外国化学品的毒害作用。最近的工作主要集中在 肾有机阴离子转运系统，因为这个系统 确定有毒外源物质的消除程度。vbl.使用 该体系的模型底物对氨基马尿酸(PAH) 表明运输需要两个人的协调行动 独特的载体蛋白。一种调节外部多环芳烃的交换 对于内部的戊二酸(或α-酮戊二酸)。第二 利用钠梯度中储存的能量将戊二酸重新驱动到 细胞，维持陡峭(进大于出)的戊二酸 推动多环芳烃吸收所需的梯度。两个系统结合在一起 间接地将BLM多环芳烃的转运耦合到钠梯度和 新陈代谢能量储存。BBM无法将这两者结合起来 流程。因此，PAH的分泌需要BLM摄取和 细胞内积累，随后多环芳烃退出其 在BBM处的电化学梯度。研究使用 电生理和放射化学技术检查 有机阳离子转运(第二大外来生物排泄物 通路)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 并且具有很强的潜在依赖性。将重点放在细胞内 事件，包括绑定、亚细胞划分和 表面膜和细胞膜之间的信息传递 细胞内细胞器、冷冻显微解剖和显微注射 在两栖类卵母细胞中开发了技术。尤其是 令人震惊的是，观察到细胞内胰岛素在剂量上 (0.5-5Pmoles)太低，不能改变表面膜的运输， 导致蛋白质和RNA合成速率的显著变化。 这些初步结果有力地证明了生理作用。 细胞内的胰岛素受体。

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.