ROLE OF ALTERED MEMBRANE FUNCTION IN XENOBIOTIC TOXICITY

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Transport of solutes across epithelial membranes is a vital function of many organs, e.g., kidney, choroid plexus, liver and gut. Epithelial transport depends upon individual transport systems located in apical (BBM) and basolateral (BLM) membranes. Their complex organization, functional importance and exposed location make epithelial membranes particularly susceptible to toxic effects of foreign chemicals. Recent research has focussed on the mechanism and energetics of renal organic anion (OA) transport system, which determines how effectively many toxic xenobiotics are excreted from the body. Isolated BLM vesicles were used to demonstrate that OA entry was driven by the inwardly directed sodium gradient, but only in the presence of glutarate (GA) or alpha-ketoglutarate (cKG). This system appears to function through uptake of OA in exchange for internal GA or alphaKG. The GA or alphaKG is returned to the interior via sodium cotransport, maintaining the outwardly directed GA (alphaKG) gradient needed to drive net OA accumulation. Thus, coupling to the sodium gradient is indirect, an example of tertiary active transport. Renal BBM vesicles from several species were used to show that exit of OA into the tubular lumen is much simpler, mediated by a carrier which can exchange internal OA for lumenal anions, largely chloride or bicarbonate. Whole tissue preparations from rat and flounder kidney and crustacean urinary bladder have demonstrated the presence of GA(alphaKG)/Na driven OA transport across the BLM into the intact epithelium. Furthermore, recent studies using the fluorescent OA, fluorescein, has permitted direct demonstration of Na/GA-dependent OA transport across the intact renal epithelium of the flounder into the lumenal compartment, i.e., that transepithelial transport is controlled by the basolateral uptake step as predicted by the earlier vesicle studies. Finally, as an initial step in assessing the control of the coupled system and biochemical characterization of the transporters involved in this system, renal m-RNA carrying the message for the OA system has been expressed in Xenopus oocytes.