Organic anion transporter 6 ( Slc22a20 ) exhibits novel substrate specificity within the organic anion transporter family

We recently demonstrated that organic anion transporter 6 [Oat6 ( Slc22a20 )], a member of the organic anion transporter (OAT) family, mediates the transport of organic anions (e.g., estrone sulfate; ES). In the present study we further characterized Oat6‐mediated transport using a stably transfected Chinese Hamster Ovary cell line. Although we previously demonstrated strong inhibition of Oat6‐mediated ES transport by p ‐aminohippurate, salicylate, and 2,4‐dichlorophenoxyacetate, when examined directly as radiolabeled substrates in this study no appreciable transport was detected. Thus, while these substrates inhibit Oat6, unlike Oat1‐3, they are not efficiently transported by Oat6. Further inhibition studies were conducted with other identified Oat1‐3 substrates including neurotransmitter metabolites, steroid hormone metabolites, and uremic toxins. Inhibition of ES accumulation by the dopamine metabolites homovanillic acid (Ki = 4.0 ± 0.3 μM) and 3,4‐dihydroxyphenylacetic acid (DOPAC; Ki = 68.0 ± 4.1 μM), and the serotonin metabolite 5‐hydroxyindole acetic acid (Ki = ~33 μM), was observed. Like Oat3, dehydroepiandrosterone (Ki = ~41 μM) and hippurate (Ki = ~66 μM) effectively inhibited Oat6‐mediated ES uptake. These data help to further elucidate the role of Oat6 in the disposition of organic anions and more precisely define its substrate specificity with respect to other members of the OAT family.