ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

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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.