ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

点击翻译按钮获取中文摘要

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.