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Relative contribution of OAT and OCT transporters to organic electrolyte transport in rabbit proximal tubule

¹Department of Physiology, College of Medicine, University of Arizona, Tucson, Arizona 85724; ²Zentrum für Physiologie und Pathophysiologie, Abteilung Vegetative Physiologie, Universität Göttingen, 37073 Göttingen, Germany; and ³Department of Physiology, Mahidol University, Bangkok 10700, Thailand

Submitted 30 April 2004 ; accepted in final form 7 July 2004

We compared the characteristics of several cloned rabbit organic electrolyte (OE) transporters expressed in cultured cells with their behavior in intact rabbit renal proximal tubules (RPT) to determine the contribution of each to basolateral uptake of the weak acid ochratoxin A (OTA) and the weak base cimetidine (CIM). The activity of organic anion transporters OAT1 and OAT3 proved to be distinguishable because OAT1 had a high affinity for PAH (K_t of 20 µM) and did not support estrone sulfate (ES) transport, whereas OAT3 had a high affinity for ES (K_t of 4.5 µM) and a weak interaction with PAH (IC₅₀ > 1 mM). In contrast, both transporters robustly accumulated OTA. Intact RPT also accumulated OTA, with OAT1 and OAT3 each responsible for 50%: ES and PAH each reduced uptake by 50%, and the combination of the two eliminated mediated OTA uptake. The weak base CIM was transported by OAT3 (K_t of 80 µM) and OCT2 (K_t of 2 µM); OCT1 had a comparatively low affinity for CIM, and CIM uptake by OAT1 was equivocal. Intact RPT accumulated CIM, with TEA and ES reducing CIM uptake by 20 and 75%, respectively, suggesting that OAT3 plays a quantitatively more significant role in CIM uptake in the early proximal tubule than OCT1/2. In single S2 segments of RPT, ES and TEA each blocked 50% of CIM uptake. Thus the fractional contribution of different OE transporters to renal secretion is influenced by their affinity for substrate and relative expression level in RPT.

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