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1 Department of Physiology, College of Medicine, University of Arizona, Tucson, AZ, USA
2 Zentrum fur Physiologie und Pathophysiologie, University of Goettingen, Goettingen, Germany
3 Department of Physiology, Mahidol University, Bangkok, Thailand
* To whom correspondence should be addressed. E-mail: shwright{at}u.arizona.edu.
We compared the characteristics of several cloned rabbit organic electrolyte (OE) transporters expressed in cultured cells to 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 OAT1 and OAT3 proved to be distinguishable because OAT1 had a high affinity for p-aminohippurate (PAH; Kt of 20 µM) and did not support estrone sulfate (ES) transport, whereas OAT3 had a high affinity for ES (Kt 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 about 50%: ES and PAH each reduced uptake by about 50%, and the combination of the two eliminated mediated OTA uptake. The weak base CIM was transported by OAT3 (Kt of 80 µM) and OCT2 (Kt of 2 µM); OCT1 had a comparatively low affinity for CIM, and CIM uptake by OAT1 was equivocal. Intact RPT accumulated CIM, with tetraethylammonium (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 about 50% of CIM uptake. Thus, the fractional contribution of different OE transporters to renal secretion is influenced by affinity for substrate and relative expression level in RPT.
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