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.

Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes

“…Functionally, PFAS share some common features with bile acids, which are key metabolites involved in the digestion and absorption of lipids in the small intestine as well as in the maintenance of lipid and glucose homeostasis 21 . Bile acids are excreted into the intestine and reabsorbed, and similar enterohepatic circulation has been suggested for PFOS and PFOA 22,23 . It has been estimated that over 90% of PFOS and PFOA have to be reabsorbed in order to explain the long half-life of these compounds in humans 24,25 .…”

Simultaneous determination of perfluoroalkyl substances and bile acids in human serum using ultra-high-performance liquid chromatography–tandem mass spectrometry

“…Biologically, the two compound groups share some common features. It is well known that BAs that are excreted into the intestine are reabsorbed, and similar enterohepatic circulation has been suggested for PFASs [8,9].…”

“…Indeed, PFAS exposure has been shown to cause alteration in gut microbiota, with higher exposure to PFAS associated with reduced microbiome diversity [20]. On the other hand, the decreased fecal BA excretion, linked with PFAS exposure [11], may be nonexclusively due to inhibition of the biosynthesis of the BAs [8,21,10] or due to the increased uptake of BAs in the gut. It has been shown that PFOA inhibits the function of the hepatocyte nuclear factor 4α [22], which plays a central role in the regulation of BA metabolism in the liver, and is linked both with the synthesis and conjugation of primary BAs.…”

Tissue toxicokinetics of perfluoro compounds with single and chronic low doses in male rats

“…Thus, the saturable active uptake of the hepatocyte may also contribute to the high hepatic accumulation of C8A in this experiment. Zhao et al (2015) investigated the transport of C8S in human embryonic kidney (HEK) 293 cells transiently expressing rat Na+/taurocholate cotransporting polypeptide (NTCP), and rat apical sodium-dependent bile salt transporter (ASBT). The results demonstrated that rat NTCP can transport C8S, whereas rat ASBT did not transport C8S.…”