ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

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The ability to transport solutes across epithelial membranes is vital for the function of many organs, e.g., secretion and reabsorption by the kidney. In turn, epithelial transport depends upon the coordinated function of individual transport systems located at opposite poles of the cells in the apical (BBM) and basolateral (BLM) membranes. Many of these membrane processes, particularly for anions, are not yet understood. Furthermore, because of their complex organization, functional importance, and exposed location, epithelial membranes are particularly susceptible to toxic effects of foreign chemicals. Our major recent emphasis has been on increasing our understanding of vectorial solute transport in polar epithelia, including the properties of specific carrier systems, the driving forces energizing transport, the regulation of transport events, and the coupling between events at opposite poles of the cells. Results for both organic (glucose, amino acids, organic acids) and inorganic (Na&, Cl minus, S04=) solutes emphasize the complexity of the chains of events which lead to active solute transport by epithelia and thus indicate that there are multiple sites for potential disruption by xenobiotics. Moreover, they also show that similar chains are responsible for transport of widely different solutes; thus, that the same mechanism may be responsible for breakdown in transport of unrelated solutes. For example, the organic cation, L-lysine, and the inorganic anion S04=, were shown to be transported via pH gradient-dependent mechanisms. Therefore, transport of both solutes could be markedly inhibited by the protonophore, pentachlorophenol, which collapses the pH gradient across the membrane.