Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier.

Sumio Ohtsuki, Tazuru Kikkawa, Shinobu Mori, Satoko Hori, Hitomi Takanaga, Masaki Otagiri, Tetsuya Terasaki

Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, New Industry Creation Hatchery Center, Tohoku University, Sendai, Japan.

The Journal of pharmacology and experimental therapeutics 2004 Jun

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The "reduced in osteosclerosis" transporter (Roct), which shows decreased expression in the osteosclerosis (oc) mutant mouse, has high homology with rat and human organic anion transporter 3 (OAT3). However, its transport properties and involvement in bone turnover are poorly understood. Here, we examined Roct-mediated transport using a Xenopus laevis oocyte expression system. Roct-expressing oocytes exhibited uptake of [(3)H]estrone sulfate, [(3)H]p-aminohippuric acid, [(3)H]benzylpenicillin, [(3)H]estradiol 17beta-glucronide, [(3)H]indoxyl sulfate, [(14)C]indomethacin, [(3)H]homovanillic acid, [(3)H]cimetidine, [(14)C]glutarate, [(14)C]salicylic acid, and [(3)H]methotrexate. Furthermore, the uptake of [(3)H]benzylpenicillin by Roct coexpressed with Na(+)-dicarboxylate cotransporter was trans-stimulated by glutarate preloading, and [(3)H]estrone sulfate uptake showed a similar tendency, suggesting that Roct is a dicarboxylate exchanger. [(3)H]Benzylpenicillin uptake by Roct was inhibited by OAT3 substrates and inhibitors, and by sulfate or glucuronide conjugates, and compounds involved in bone turnover. Roct mRNA is expressed abundantly in the kidney and was also detected in the brain, choroid plexus, and eye. Immunohistochemical analysis revealed that Roct is localized in brain capillary endothelial cells. These results indicate that the transport properties and tissue distribution of Roct are similar to those of OAT3, suggesting that Roct functions as mouse OAT3. Because Roct is expressed in the kidney and at the blood-brain barrier, it may play a role in the excretion of substrates such as conjugates and bone turnover factors.

Citation

Sumio Ohtsuki, Tazuru Kikkawa, Shinobu Mori, Satoko Hori, Hitomi Takanaga, Masaki Otagiri, Tetsuya Terasaki. Mouse reduced in osteosclerosis transporter functions as an organic anion transporter 3 and is localized at abluminal membrane of blood-brain barrier. The Journal of pharmacology and experimental therapeutics. 2004 Jun;309(3):1273-81