RENAL ORGANIC CATION--SPECIFICITY AND ENERGETICS

Organic cations (and bases; collectively, "OCs") comprise a diverse array of molecules of physiological, pharmacological, and toxicological relevance. The transport processes in the kidney, particularly in the proximal tubule, play a major role in regulating levels of these compounds in the body. We seek an understanding of the mechanisms by which organic cations enter, leave, and are accumulated within renal calls. In particular, we are interested in how the diverse structures of this broad array of compounds influence their ability to interact, i.e., bind to and then be translocated by, transporters in proximal tubule cells, and in the energetics of transepithelial OC transport and intracellular accumulation of these compounds. Our proposed studies with intact tubules, cultured cells, and subcellular membrane fractions isolated from rabbit kidney will combine traditional radiotracer techniques and novel optical methods for measuring transport. The experiments outlined here will test several hypotheses proposing, in general, that: (a) there is a systematic relationship between efficacy of binding and subsequent transport of substrates by OC transporters; (b) the integrated activity of the several luminal and peritubular OC transporters results in the secretion of some OCs and the reabsorption of others; and (c) a substantial fraction of accumulated OCs is sequestered within an endosomally-derived population of intracellular membrane vesicles. Through an understanding of the mechanisms associated with the renal transport and accumulation of xenobiotic OCs we expect to develop the first predictive model for the specificity of a transepithelial renal OC transport pathway and provide the first definitive tests in intact tubules of current proposals for how OCs are transported by the proximal tubule.