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. Isolated BBM and BLM vesicles are used to examine cell membrane events. Intact epithelial preparations, including teleost renal tubules and crustacean urinary bladder, allow assessment of electrical and transport properties and permit study of regulatory mechanisms. Cryomicrodissection of intact amphibian oocytes permits direct analysis of solute activities in a living cell. Results in mammals, lowers vertebrates and crustaceans demonstrated the intricate interrelations between solute transport, ion gradients and metabolic energy transduction. Transport may, therefore, be disrupted by xenobiotics at multiple sites in these complex chains of events. However, certain features of these events are common to the transport of several solutes. Thus, the same mechanism may account for impaired transport of multiple solutes, e.g., collapse of proton gradients by pentachlorophenol or of the sodium gradient by ouabain lead to reduced transport of numerous solutes whose secondary active transport is energized by these gradients.