ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

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Transport of solutes across polar epithelia is required for function of many organs, e.g., kidney. In turn, epithelial transport depends upon the coordinated function of transport proteins in apical and basal poles of these cells. In recent years, we have examined the mechanism and energetics of renal organic anion (OA) transport, the major system which governs the elimination of foreign chemicals, demonstrating its indirect coupling to metabolic energy through Na/alpha-ketoglutarate (alphaKG) co- transport and OA/alphaKG exchange. Our current focus is on the intracellular and luminal events associated with OA transport, the mechanism(s) of OA transport in extrarenal tissues, and the molecular biology of the OA system. Isolated luminal membrane vesicles show both anion exchange and carrier-mediated, potential-driven pathways. However, only the potential-driven pathway appears to mediate luminal exit of secreted OA. Interestingly, during secretion OA show punctate accumulation within the cytoplasm. This process is energy dependent and saturable. Its relation to net transport is under investigation. Extrarenal tissues (liver and choroid plexus) also appear to utilize indirect Na coupling to drive OA transport. However, this appears to be substrate specific, e.g., fluorescein, but not 2,4-dichlorophenoxyacetic acid, in the choroid plexus and taurocholate, but not bile pigments, in the liver, show Na/alphaOG coupled transport. The basis for these differences is under study. Finally, initial steps in expression cloning of the renal OA transport proteins have been completed and a cDNA library is currently being screened to identify clones which carry nucleotides encoding these transport proteins. Once isolated these nucleotides will provide probes for investigation of the control, development, and distribution of this important excretory transport system.