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Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)

Poly- and perfluoroalkyl substances (PFASs) are omnipresent in the environment and have been shown to accumulate in humans. Most PFASs are not biotransformed in animals and humans, so that elimination is largely dependent on non-metabolic clearance via bile and urine. Accumulation of certain PFASs i...

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Autores principales: Louisse, Jochem, Dellafiora, Luca, van den Heuvel, Jeroen J. M. W., Rijkers, Deborah, Leenders, Liz, Dorne, Jean-Lou C. M., Punt, Ans, Russel, Frans G. M., Koenderink, Jan B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer Berlin Heidelberg 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968691/
https://www.ncbi.nlm.nih.gov/pubmed/36436016
http://dx.doi.org/10.1007/s00204-022-03428-6
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author Louisse, Jochem
Dellafiora, Luca
van den Heuvel, Jeroen J. M. W.
Rijkers, Deborah
Leenders, Liz
Dorne, Jean-Lou C. M.
Punt, Ans
Russel, Frans G. M.
Koenderink, Jan B.
author_facet Louisse, Jochem
Dellafiora, Luca
van den Heuvel, Jeroen J. M. W.
Rijkers, Deborah
Leenders, Liz
Dorne, Jean-Lou C. M.
Punt, Ans
Russel, Frans G. M.
Koenderink, Jan B.
author_sort Louisse, Jochem
collection PubMed
description Poly- and perfluoroalkyl substances (PFASs) are omnipresent in the environment and have been shown to accumulate in humans. Most PFASs are not biotransformed in animals and humans, so that elimination is largely dependent on non-metabolic clearance via bile and urine. Accumulation of certain PFASs in humans may relate to their reabsorption from the pre-urine by transporter proteins in the proximal tubules of the kidney, such as URAT1 and OAT4. The present study assessed the in vitro transport of 7 PFASs (PFHpA, PFOA, PFNA, PFDA, PFBS, PFHxS and PFOS) applying URAT1- or OAT4-transfected human embryonic kidney (HEK) cells. Virtually no transport of PFASs could be measured in URAT1-transfected HEK cells. All PFASs, except PFBS, showed clear uptake in OAT4-transfected HEK cells. In addition, these in vitro results were further supported by in silico docking and molecular dynamic simulation studies assessing transporter–ligand interactions. Information on OAT4-mediated transport may provide insight into the accumulation potential of PFASs in humans, but other kinetic aspects may play a role and should also be taken into account. Quantitative information on all relevant kinetic processes should be integrated in physiologically based kinetic (PBK) models, to predict congener-specific accumulation of PFASs in humans in a more accurate manner. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03428-6.
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spelling pubmed-99686912023-02-28 Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4) Louisse, Jochem Dellafiora, Luca van den Heuvel, Jeroen J. M. W. Rijkers, Deborah Leenders, Liz Dorne, Jean-Lou C. M. Punt, Ans Russel, Frans G. M. Koenderink, Jan B. Arch Toxicol Toxicokinetics and Metabolism Poly- and perfluoroalkyl substances (PFASs) are omnipresent in the environment and have been shown to accumulate in humans. Most PFASs are not biotransformed in animals and humans, so that elimination is largely dependent on non-metabolic clearance via bile and urine. Accumulation of certain PFASs in humans may relate to their reabsorption from the pre-urine by transporter proteins in the proximal tubules of the kidney, such as URAT1 and OAT4. The present study assessed the in vitro transport of 7 PFASs (PFHpA, PFOA, PFNA, PFDA, PFBS, PFHxS and PFOS) applying URAT1- or OAT4-transfected human embryonic kidney (HEK) cells. Virtually no transport of PFASs could be measured in URAT1-transfected HEK cells. All PFASs, except PFBS, showed clear uptake in OAT4-transfected HEK cells. In addition, these in vitro results were further supported by in silico docking and molecular dynamic simulation studies assessing transporter–ligand interactions. Information on OAT4-mediated transport may provide insight into the accumulation potential of PFASs in humans, but other kinetic aspects may play a role and should also be taken into account. Quantitative information on all relevant kinetic processes should be integrated in physiologically based kinetic (PBK) models, to predict congener-specific accumulation of PFASs in humans in a more accurate manner. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00204-022-03428-6. Springer Berlin Heidelberg 2022-11-27 2023 /pmc/articles/PMC9968691/ /pubmed/36436016 http://dx.doi.org/10.1007/s00204-022-03428-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Toxicokinetics and Metabolism
Louisse, Jochem
Dellafiora, Luca
van den Heuvel, Jeroen J. M. W.
Rijkers, Deborah
Leenders, Liz
Dorne, Jean-Lou C. M.
Punt, Ans
Russel, Frans G. M.
Koenderink, Jan B.
Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title_full Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title_fullStr Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title_full_unstemmed Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title_short Perfluoroalkyl substances (PFASs) are substrates of the renal human organic anion transporter 4 (OAT4)
title_sort perfluoroalkyl substances (pfass) are substrates of the renal human organic anion transporter 4 (oat4)
topic Toxicokinetics and Metabolism
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9968691/
https://www.ncbi.nlm.nih.gov/pubmed/36436016
http://dx.doi.org/10.1007/s00204-022-03428-6
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