Identification of 2,4‐dichlorophenoxyacetate and glutamate as novel substrates for murine organic anion transporter 2 ( Slc22a7 )

Organic anion transporter 2 [Oat2 ( Slc22a7 )], which is found in kidney and liver, exhibits profound species differences in expression level and substrate specificity. Therefore, we used Oat2‐expressing Xenopus oocytes to better elucidate the function of Oat2 in the murine model system. We demonstrated that mouse Oat2 (mOat2) mediates the transport of the previously unknown substrates 2,4‐dichlorophenoxyacetate (2,4‐D), glutamate, and salicylate, as well as, the known substrate ochratoxin A (OTA). Transport of 2,4‐D, glutamate, salicylate, and OTA was markedly inhibited by probenecid (approximately 65%, 50%, 65% and 90%, respectively) and by L‐glutamate (approximately 70%, 90%, 45% and 80%, respectively), but not by D‐glutamate. Interaction of neurotransmitter metabolites, steroid hormone metabolites, and uremic toxins with mOat2 was also investigated. mOat2‐mediated transport was inhibited by 3,4‐dihydroxyphenylacetate (DOPAC), but unlike Oat3, not by homovanillic acid or 5‐hydroxyindole acetic acid. Like Oat3, dehydroepiandrosterone sulfate inhibited mOat2 transport, but in contrast to Oat3, estrone sulfate did not. Finally, unlike the renal exchangers Oat1 and Oat3, neither indoxyl sulfate nor hippuric acid inhibited mOat2 transport. These data suggest that mOat2 is poised to play a unique role in the renal and hepatic detoxification and elimination of endogenous and xenobiotic substrates.