In recent years, we have examined the mechanism and energetics of renal organic anion (OA) and cation (OC) transport. These are the primary systems which govern the elimination of foreign chemicals. OA transport was shown to be indirectly coupled to metabolic energy through Na/alpha- ketoglutarate (alphaKG) co-transport and OA/alphaKG exhange. We are currently examinng both plasma membrane and intracellular events associated with secretory transport and initiating studies of the molecular biology of these systems. This work indicates that the rate of OA transport may be modulated by manipulations which alter either the internal alphaKG concentration or its in-to-out gradient. In addition, imaging studies indicate that sequestration within intracellular vesicles reduces the cytoplasmic OA concentrations, apparently protecting intracellular sites during secretion. Sequestration of OA is both carrier mediated and energy dependent. OC are also sequestered, suggesting that vesicular packaging may be a general means of protecting transporting epithelial cells during secretion. The mechanism of OC sequestration was a secondary active proton/OC exchange, driven by a proton-ATPase present in these endosomal vesicles. Initial evidence indicates that these vesicles move in a basolateral to apical direction, raising the possibility that they may also play a direct role in transcellular movement of secreted xenobiotics. Expression cloning techniques are currently in use to identify and clone specific membrane proteins responsible for individual transport steps in secretion of foreign anions and cations. Finally, cell culture techniques have been applied to develop intact epithelial sheet preparations for analysis of these transport systems, their control mechanisms, and their sensitivity to xenobiotic toxicity. These studies have shown for the first time that a renal line (the OK cell) demonstrates OA secretion and in comparison with primary cultures of rat proximal tubule, they provide a means to analyze control of transepithelial OA and OC transport in intact epithelial.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES080031-17
Application #
3777564
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
17
Fiscal Year
1993
Total Cost
Indirect Cost
City
State
Country
United States
Zip Code
Srimaroeng, Chutima; Cecile, Jennifer Perry; Walden, Ramsey et al. (2013) Regulation of renal organic anion transporter 3 (SLC22A8) expression and function by the integrity of lipid raft domains and their associated cytoskeleton. Cell Physiol Biochem 31:565-78
Barros, Scott A; Srimaroeng, Chutima; Perry, Jennifer L et al. (2009) Activation of protein kinase Czeta increases OAT1 (SLC22A6)- and OAT3 (SLC22A8)-mediated transport. J Biol Chem 284:2672-9
Srimaroeng, C; Perry, J L; Pritchard, J B (2008) Physiology, structure, and regulation of the cloned organic anion transporters. Xenobiotica 38:889-935
Bow, Daniel A J; Perry, Jennifer L; Miller, David S et al. (2008) Localization of P-gp (Abcb1) and Mrp2 (Abcc2) in freshly isolated rat hepatocytes. Drug Metab Dispos 36:198-202
Kimura, T; Perry, J; Anzai, N et al. (2007) Development and characterization of immobilized human organic anion transporter-based liquid chromatographic stationary phase: hOAT1 and hOAT2. J Chromatogr B Analyt Technol Biomed Life Sci 859:267-71
Aslamkhan, Amy G; Thompson, Deborah M; Perry, Jennifer L et al. (2006) The flounder organic anion transporter fOat has sequence, function, and substrate specificity similarity to both mammalian Oat1 and Oat3. Am J Physiol Regul Integr Comp Physiol 291:R1773-80
Bow, Daniel A J; Perry, Jennifer L; Simon, John D et al. (2006) The impact of plasma protein binding on the renal transport of organic anions. J Pharmacol Exp Ther 316:349-55
Perry, Jennifer L; Dembla-Rajpal, Neetu; Hall, Laura A et al. (2006) A three-dimensional model of human organic anion transporter 1: aromatic amino acids required for substrate transport. J Biol Chem 281:38071-9
Srimaroeng, Chutima; Chatsudthipong, Varanuj; Aslamkhan, Amy G et al. (2005) Transport of the natural sweetener stevioside and its aglycone steviol by human organic anion transporter (hOAT1; SLC22A6) and hOAT3 (SLC22A8). J Pharmacol Exp Ther 313:621-8
Pritchard, John B; Miller, David S (2005) Expression systems for cloned xenobiotic transporters. Toxicol Appl Pharmacol 204:256-62

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