title: Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats.
abstract: Perfluoroalkyl sulfonates (PFSAs) such as perfluorohexane sulfonate (PFHxS) and perfluorooctane sulfonate (PFOS) have very long serum elimination half-lives in humans, and preferentially distribute to serum and liver. The enterohepatic circulation of PFHxS and PFOS likely contributes to their extended elimination half-lives. We previously demonstrated that perfluorobutane sulfonate (PFBS), PFHxS, and PFOS are transported into hepatocytes both in a sodium-dependent and a sodium-independent manner. We identified Na+/taurocholate cotransporting polypeptide (NTCP) as the responsible sodium-dependent transporter. Furthermore, we demonstrated that the human apical sodium-dependent bile salt transporter (ASBT) contributes to the intestinal reabsorption of PFOS. However, so far no sodium-independent uptake transporters for PFSAs have been identified in human hepatocytes or enterocytes. In addition, perfluoroalkyl carboxylates (PFCAs) with 8 and 9 carbons were shown to preferentially distribute to the liver of rodents; however, no rat or human liver uptake transporters are known to transport these PFCAs. Therefore, we tested whether PFBS, PFHxS, PFOS, and PFCAs with 7-10 carbons are substrates of organic anion transporting polypeptides (OATPs). We used CHO and HEK293 cells to demonstrate that human OATP1B1, OATP1B3, and OATP2B1 can transport PFBS, PFHxS, PFOS, and the 2 PFCAs (C8 and C9). In addition, we show that rat OATP1A1, OATP1A5, OATP1B2, and OATP2B1 transport all 3 PFSAs. In conclusion, our results suggest that besides NTCP and ASBT, OATPs also are capable of contributing to the enterohepatic circulation and extended human serum elimination half-lives of the tested perfluoroalkyl acids.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Wen
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Pace Analytical Services, Minneapolis, Minnesota 55414.|Medical Department, 3M Company, St Paul, Minnesota 55144.
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Zitzow
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Yi
authors.initials: Y
authors.lastname: Weaver
authors.affiliation: Medical Department, 3M Company, St Paul, Minnesota 55144.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ehresman
authors.affiliation: Medical Department, 3M Company, St Paul, Minnesota 55144.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Chang
authors.affiliation: SaluTox, LLC, Lake Elmo, Minnesota 55042.
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, Kansas 66160.
authors.forename: Bruno
authors.initials: B
authors.lastname: Hagenbuch
mesh_terms: D017738:Alkanesulfonic Acids / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport; D016466:CHO Cells; D002210:Caprylates / Q000378:metabolism; D003412:Cricetulus; D004785:Environmental Pollutants / Q000378:metabolism*; D005466:Fluorocarbons / Q000378:metabolism*; D057809:HEK293 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1 / Q000235:genetics / Q000378:metabolism*; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3 / Q000235:genetics / Q000378:metabolism*; D013451:Sulfonic Acids / Q000378:metabolism
chemical_list: D017738:Alkanesulfonic Acids; D002210:Caprylates; D004785:Environmental Pollutants; D005466:Fluorocarbons; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; D011993:Recombinant Fusion Proteins; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D013451:Sulfonic Acids; C000609070:Oatp1a1 protein, rat; C503999:SLCO1B1 protein, human; C421209:SLCO1B3 protein, human; C450859:SLCO2B1 protein, human; C421143:Slco1a5 protein, rat; C421207:Slco1b2 protein, rat; C533062:Slco2b1 protein, rat; C539348:perfluorobutanesulfonic acid; C471071:perfluorohexanesulfonic acid; C018959:hexadecafluoro-nonanoic acid; C023036:perfluorooctanoic acid; C076994:perfluorooctane sulfonic acid
keywords: perfluoroalkyl carboxylates.; perfluoroalkyl sulfonates; perfluorobutane sulfonate; perfluorohexane sulfonate; perfluorooctane sulfonate