title: Na+/Taurocholate Cotransporting Polypeptide and Apical Sodium-Dependent Bile Acid Transporter Are Involved in the Disposition of Perfluoroalkyl Sulfonates in Humans and Rats.
abstract: Among the perfluoroalkyl sulfonates (PFASs), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) have half-lives of several years in humans, mainly due to slow renal clearance and potential hepatic accumulation. Both compounds undergo enterohepatic circulation. To determine whether transporters involved in the enterohepatic circulation of bile acids are also involved in the disposition of PFASs, uptake of perfluorobutane sulfonate (PFBS), PFHxS, and PFOS was measured using freshly isolated human and rat hepatocytes in the absence or presence of sodium. The results demonstrated sodium-dependent uptake for all 3 PFASs. Given that the Na(+)/taurocholate cotransporting polypeptide (NTCP) and the apical sodium-dependent bile salt transporter (ASBT) are essential for the enterohepatic circulation of bile acids, transport of PFASs was investigated in stable CHO Flp-In cells for human NTCP or HEK293 cells transiently expressing rat NTCP, human ASBT, and rat ASBT. The results demonstrated that both human and rat NTCP can transport PFBS, PFHxS, and PFOS. Kinetics with human NTCP revealed Km values of 39.6, 112, and 130 µM for PFBS, PFHxS, and PFOS, respectively. For rat NTCP Km values were 76.2 and 294 µM for PFBS and PFHxS, respectively. Only PFOS was transported by human ASBT whereas rat ASBT did not transport any of the tested PFASs. Human OSTα/β was also able to transport all 3 PFASs. In conclusion, these results suggest that the long half-live and the hepatic accumulation of PFOS in humans are at least, in part, due to transport by NTCP and ASBT.
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;
authors.forename: Jeremiah D
authors.initials: JD
authors.lastname: Zitzow
authors.affiliation: Medical Department, 3M Company, St. Paul, Minnesota 55144; and.
authors.forename: David J
authors.initials: DJ
authors.lastname: Ehresman
authors.affiliation: Medical Department, 3M Company, St. Paul, Minnesota 55144; and.
authors.forename: Shu-Ching
authors.initials: SC
authors.lastname: Chang
authors.affiliation: Medical Department, 3M Company, St. Paul, Minnesota 55144; and bhagenbuch@kumc.edu.
authors.forename: John L
authors.initials: JL
authors.lastname: Butenhoff
authors.affiliation: Department of Surgery, The University of Kansas Medical Center, Kansas City, KS 66160.
authors.forename: Jameson
authors.initials: J
authors.lastname: Forster
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 / Q000493:pharmacokinetics*; D000818:Animals; D005466:Fluorocarbons / Q000493:pharmacokinetics*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D029363:Organic Anion Transporters, Sodium-Dependent / Q000502:physiology*; D051381:Rats; D013451:Sulfonic Acids / Q000493:pharmacokinetics*; D027981:Symporters / Q000502:physiology*
chemical_list: D017738:Alkanesulfonic Acids; D005466:Fluorocarbons; D029363:Organic Anion Transporters, Sodium-Dependent; D013451:Sulfonic Acids; D027981:Symporters; C071908:sodium-bile acid cotransporter; C471071:perfluorohexanesulfonic acid; C076994:perfluorooctane sulfonic acid; C108042:perfluorobutane
keywords: hepatocytes; perfluoroalkyl sulfonates; perfluorobutane sulfonate; perfluorohexane sulfonate; perfluorooctane sulfonate