EXPRESSION CLONING AND CHARACTERIZATION OF A NOVEL MULTISPECIFIC ORGANIC ANION TRANSPORTER

Numerous drugs and endogenous compounds are efficiently excreted from the renal proximal tubule via carrier-mediated pathways. Transepitheli al excretion of organic anions occurs via their accumulative transport from the blood into the proximal tubule cells across the basolateral membrane and subsequent secretion into the urine through the apical me mbrane. Here we report on the isolation of a novel complementary DNA f rom rat kidney that encodes a 551-amino acid residue protein (OAT1) wi th 12 putative membrane-spanning domains. When expressed in Xenopus la evis oocytes, OAT1 mediated sodium-independent para-aminohippurate (PA H) uptake (K-m = 14.3 +/- 2.9 mu M). The uptake rate of PAH was increa sed by the outwardly directed dicarboxylate gradient, consisting with the idea that OAT1 is an organic anion/dicarboxylate exchanger, OAT1 d isplayed remarkably wide substrate selectivity, covering endogenous su bstrates such as cyclic nucleotides, a prostaglandin and uric acid, an d a variety of drugs with different structures (e.g. antibiotics, a no nsteroidal antiinflammatory drug, diuretics, an antineoplastic drug, a nd a uricosuric drug). The Northern blot analysis and in situ hybridiz ation revealed that OAT1 is exclusively expressed in the particular se gment of the proximal tubule in the kidney. These data suggest that OA T1 is a multispecific organic anion transporter at the basolateral mem brane of the proximal tubule. Isolation of OAT1 will facilitate elucid ation of the molecular basis of drug kinetics and the development of n ew drugs lacking unwanted side effects.