Ids Interact with the Human Bile Acid Transporter NTCPMelissa J. Ruggiero
Ids Interact with all the Human Bile Acid Transporter NTCPMelissa J. Ruggiero 1 , Haley Miller 1 , Jessica Y. Idowu 1 , Jeremiah D. Zitzow 2 , Shu-Ching Chang two and Bruno Hagenbuch 1, Division of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA; [email protected] (M.J.R.); [email protected] (H.M.); [email protected] (J.Y.I.) Health-related Division, 3M Corporation, St Paul, MN 55144, USA; [email protected] (J.D.Z.); [email protected] (S.-C.C.) Correspondence: [email protected]; Tel.: +1-913-588-Citation: Ruggiero, M.J.; Miller, H.; Idowu, J.Y.; Zitzow, J.D.; Chang, S.-C.; Hagenbuch, B. Perfluoroalkyl Carboxylic Acids Interact with the Human Bile Acid Transporter NTCP. Livers 2021, 1, 22129. https:// doi.org/10.3390/livers1040017 Academic Editor: Mitchell R. McGill Received: 23 August 2021 Accepted: 13 October 2021 Published: 18 OctoberAbstract: Na+ /taurocholate cotransporting polypeptide (NTCP) is important for the enterohepatic circulation of bile acids, which has been recommended to contribute to the lengthy serum elimination halflives of perfluoroalkyl substances in humans. We GSK2646264 In Vivo demonstrated that some perfluoroalkyl sulfonates are transported by NTCP; even so, small was identified 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 [3 H]-taurocholate was measured in human embryonic kidney cells (HEK293) stably expressing NTCP within the absence or presence of perfluoroalkyl carboxylates with varying chain lengths. PFCAs with 8 (PFOA), 9 (PFNA), and ten (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 3 compounds are transported by NTCP, and kinetics experiments revealed that PFOA had the highest affinity for NTCP with a Km worth of 1.8 0.4 mM. The Km worth PFNA was estimated to become five.3 3.5 mM and the value for PFDA could not be determined as a consequence of limited solubility. In conclusion, our final results suggest that, also to sulfonates, perfluorinated carboxylates are substrates of NTCP and have the potential to interact with NTCP-mediated transport. Key phrases: perfluoroalkyl acids; perfluoroalkyl carboxylates; taurocholate Goralatide Biological Activity transport1. Introduction Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are fluorinated fatty acid-like molecules that have been utilised in a range of industrial applications [1]. Among them, perfluoroalkyl carboxylates (PFCAs) are a subset of PFAS compounds that don’t undergo further degradation, therefore they are often deemed because the end-stage metabolites from the related precursor chemistries [2]. PFCAs are persistent due to chemical stability [3] and a few of them may be detected in humans at low components per billion levels [6]. While the exact exposure routes haven’t been identified in the basic population, dietary ingestion (food or water) has been recommended as the main source of exposure to particular PFAS compounds [9]. Based on the perfluoroalkyl chain length, after absorbed, a few of the longer-chain PFCAs, for instance perfluorooctanoic acid (perfluorooctanoate, PFOA), are gradually excreted in urine and/or feces in the majority of the species evaluated. Consequently, the serum elimination half-lives for PFOA can range from days to weeks in laboratory mice and non-human primates, or, several years in hu.
