Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats

Toxicol Sci. 2017 Mar 1;156(1):84-95. doi: 10.1093/toxsci/kfw236.

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.

Keywords: perfluoroalkyl carboxylates.; perfluoroalkyl sulfonates; perfluorobutane sulfonate; perfluorohexane sulfonate; perfluorooctane sulfonate.

MeSH terms

  • Alkanesulfonic Acids / metabolism*
  • Animals
  • Biological Transport
  • CHO Cells
  • Caprylates / metabolism
  • Cricetulus
  • Environmental Pollutants / metabolism*
  • Fluorocarbons / metabolism*
  • HEK293 Cells
  • Hepatocytes / metabolism*
  • Humans
  • Liver-Specific Organic Anion Transporter 1 / genetics
  • Liver-Specific Organic Anion Transporter 1 / metabolism*
  • Organic Anion Transporters / genetics
  • Organic Anion Transporters / metabolism*
  • Organic Anion Transporters, Sodium-Independent / genetics
  • Organic Anion Transporters, Sodium-Independent / metabolism
  • Rats
  • Recombinant Fusion Proteins / metabolism
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / genetics
  • Solute Carrier Organic Anion Transporter Family Member 1B3 / metabolism*
  • Sulfonic Acids / metabolism

Substances

  • Alkanesulfonic Acids
  • Caprylates
  • Environmental Pollutants
  • Fluorocarbons
  • Liver-Specific Organic Anion Transporter 1
  • Oatp1a1 protein, rat
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Independent
  • Recombinant Fusion Proteins
  • SLCO1B1 protein, human
  • SLCO1B3 protein, human
  • SLCO2B1 protein, human
  • Slco1a5 protein, rat
  • Slco1b2 protein, rat
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Sulfonic Acids
  • oatp2b1 protein, rat
  • perfluorobutanesulfonic acid
  • perfluorohexanesulfonic acid
  • hexadecafluoro-nonanoic acid
  • perfluorooctanoic acid
  • perfluorooctane sulfonic acid