Ruggiero Melissa J, Miller Haley, Idowu Jessica Y, Zitzow Jeremiah D, Chang Shu-Ching, Hagenbuch Bruno
Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
Medical Department, 3M Company, St Paul, MN 55144, USA.
Livers. 2021 Dec;1(4):221-229. doi: 10.3390/livers1040017. Epub 2021 Oct 18.
Na/taurocholate cotransporting polypeptide (NTCP) is important for the enterohepatic circulation of bile acids, which has been suggested to contribute to the long serum elimination half-lives of perfluoroalkyl substances in humans. We demonstrated that some perfluoroalkyl sulfonates are transported by NTCP; however, little was known about carboxylates. The purpose of this study was to determine if perfluoroalkyl carboxylates would interact with NTCP and potentially act as substrates. Sodium-dependent transport of [H]-taurocholate was measured in human embryonic kidney cells (HEK293) stably expressing NTCP in the absence or presence of perfluoroalkyl carboxylates with varying chain lengths. PFCAs with 8 (PFOA), 9 (PFNA), and 10 (PFDA) carbons were the strongest inhibitors. Inhibition kinetics demonstrated competitive inhibition and indicated that PFNA was the strongest inhibitor followed by PFDA and PFOA. All three compounds are transported by NTCP, and kinetics experiments revealed that PFOA had the highest affinity for NTCP with a K value of 1.8 ± 0.4 mM. The K value PFNA was estimated to be 5.3 ± 3.5 mM and the value for PFDA could not be determined due to limited solubility. In conclusion, our results suggest that, in addition to sulfonates, perfluorinated carboxylates are substrates of NTCP and have the potential to interact with NTCP-mediated transport.
钠/牛磺胆酸盐共转运多肽（NTCP）对胆汁酸的肠肝循环很重要，有人认为这有助于人类全氟烷基物质在血清中的长消除半衰期。我们证明了一些全氟烷基磺酸盐可被NTCP转运；然而，关于羧酸盐的情况却知之甚少。本研究的目的是确定全氟烷基羧酸盐是否会与NTCP相互作用并可能作为底物。在稳定表达NTCP的人胚胎肾细胞（HEK293）中，在存在或不存在不同链长的全氟烷基羧酸盐的情况下，测量[H] - 牛磺胆酸盐的钠依赖性转运。含8个（全氟辛酸，PFOA）、9个（全氟壬酸，PFNA）和10个（全氟癸酸，PFDA）碳的全氟羧酸是最强的抑制剂。抑制动力学显示为竞争性抑制，表明PFNA是最强的抑制剂，其次是PFDA和PFOA。所有这三种化合物都可被NTCP转运，动力学实验表明PFOA对NTCP的亲和力最高，K值为1.8±0.4 mM。PFNA的K值估计为5.3±3.5 mM，由于溶解度有限，PFDA的值无法确定。总之，我们的结果表明，除了磺酸盐外，全氟羧酸盐也是NTCP的底物，并且有可能与NTCP介导的转运相互作用。
