Novel aspects of renal organic anion transporters

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Abstract
Organic anion transporters, transmembrane proteins present in the renal proximal tubule, are a critical component of the human drug excretion machinery. Recent advances have clarified the function of these transporters, with broad clinical implications for pharmacogenetics, drug interactions and adverse reactions. Here, we discuss these issues in the context of the basic biology of the transporters. Understanding of organic anion transporter function has proceeded on several fronts. The continued cataloging of organic anion transporter substrates has revealed that the transporters' activity likely underlies many common drug interactions and nephrotoxic adverse reactions. Meanwhile, immunohistochemical and physiological studies suggest their potential involvement in the apical as well as basolateral steps of renal organic anion secretion. In addition, studies of the genomic organization of these transporters reveal that they are found in pairs of similar and similarly expressed genes, suggesting that pair members are coordinately regulated. Finally, we hypothesize here that organic anion transporters might impact renal susceptibility to ischemia and toxic injury, because their uptake of substrates can result in the efflux of Krebs cycle intermediates, an important nutrient source for the proximal tubule. The study of these transporters will likely have a significant impact on renal pharmacology and pharmacogenetics. In this regard, the generation of organic anion transporter gene knockout mice could provide invaluable models for defects in renal drug-handling. Ultimately, detailed knowledge of organic anion transporter function will assist in the choice of optimum pharmacological therapies.