Department of Pharmaceutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, 2630, Sugitani, Toyama, Japan.
Graduate School of Biomedical Sciences, Tokushima University, 1-78-1, Sho-machi, Tokushima, Japan.
Drug Metab Pharmacokinet. 2019 Aug;34(4):239-246. doi: 10.1016/j.dmpk.2019.04.001. Epub 2019 Apr 11.
It has been known that organic anion-transporting polypeptides (Oatps) involve hepatic transports several organic anionic compounds and drugs. This study aimed to investigate sulforhodamine-101 (SR-101) distribution in the rat liver, determine the molecules responsible for the distribution, and delineate the manner of distribution. After intravenous SR-101 administration, its distribution in frozen rat hepatic sections was examined. SR-101-derived signals were detected in regions around the hepatic central vein (CV), where immunohistochemistry (IHC) indicated high Oatp1a4 expression. The signals decreased with treatment by digoxin, a specific substrate for Oatp1a4. In vitro studies using isolated rat hepatocytes and rat Oatp1a4-expressing Xenopus laevis oocytes have suggested that SR-101 is an Oatp1a4 substrate and is taken up into rat hepatocytes mainly via Oatp1a4. Therefore, results suggested SR-101 zonation because of Oatp1a4 involvement and that Oatp1a4 function is dominant in the region around the hepatic CV in rat hepatic lobules.
已知有机阴离子转运多肽（Oatps）参与肝脏对多种有机阴离子化合物和药物的转运。本研究旨在研究磺罗丹明 101（SR-101）在大鼠肝脏中的分布，确定负责分布的分子，并阐明分布方式。静脉注射 SR-101 后，检查冷冻大鼠肝切片中的分布情况。在肝中央静脉（CV）周围区域检测到源自 SR-101 的信号，免疫组织化学（IHC）表明该区域 Oatp1a4 表达水平较高。这些信号随着 Oatp1a4 的特异性底物地高辛的处理而减少。使用分离的大鼠肝细胞和表达大鼠 Oatp1a4 的非洲爪蟾卵母细胞的体外研究表明，SR-101 是 Oatp1a4 的底物，主要通过 Oatp1a4 进入大鼠肝细胞。因此，结果表明由于 Oatp1a4 的参与导致 SR-101 出现区域性分布，并且 Oatp1a4 功能在大鼠肝小叶的肝 CV 周围区域占主导地位。
