Perfluoroalkyl Carboxylic Acids Interact with the Human Bile Acid Transporter NTCP.

Melissa J Ruggiero,Haley Miller,Bruno Hagenbuch,Jeremiah D Zitzow,Jessica Y Idowu,Shu-Ching Chang

doi:10.3390/livers1040017

Melissa J Ruggiero, Haley Miller + Show 4 more

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https://doi.org/10.3390/livers1040017

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Journal: Livers	Publication Date: Oct 18, 2021
Citations: 18	License type: CC BY 4.0

Affiliation: University of Kansas Medical Center, 3M (United States)

Abstract

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 [3H]-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 Km value of 1.8 ± 0.4 mM. The Km 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.

Highlights

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are fluorinated fatty acid-like molecules that have been used in a variety of industrial applications [1]
Perfluoroalkyl carboxylates (PFCAs) are a subset of PFAS compounds that do not undergo further degradation, they are often considered as the end-stage metabolites of the related precursor chemistries [2]
To investigate whether perfluoroalkyl carboxylates (PFCAs) would interact with the human Na+ /taurocholate cotransporting polypeptide (NTCP), we determined to what extent perfluorinated carboxylic

Summary

Introduction

Perfluoroalkyl and polyfluoroalkyl substances (PFASs) are fluorinated fatty acid-like molecules that have been used in a variety of industrial applications [1]. Perfluoroalkyl carboxylates (PFCAs) are a subset of PFAS compounds that do not undergo further degradation, they are often considered as the end-stage metabolites of the related precursor chemistries [2]. Shorter chain PFCAs, such as perfluorobutanoic acid (perfluorobutyrate, PFBA), can be rapidly eliminated via urine and the corresponding serum elimination half-lives range from a few hours in laboratory rodents to a few days in humans [7,10].

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