Effects of perfluoroalkyl carboxylic acids on the uptake of sulfobromophthalein via organic anion transporting polypeptides in human intestinal Caco-2 cells

Abstract

We performed a detailed investigation of the uptake of sulfobromophthalein (BSP) from the apical membrane of Caco-2 cells, which is a substrate for organic anion transporting polypeptides (OATPs), and calculated the kinetic parameters of BSP uptake as follows: K m = 13.9 ± 1.3 μM, V max = 1.15 ± 0.07 nmol (mg protein) −1 (5 min) −1 , and k d = 38.2 ± 0.53 μL (mg protein) −1 (5 min) −1 . Coincubation with medium-chain (C7–C11) perfluoroalkyl carboxylic acids (PFCAs), such as perfluoroheptanoic acid (PFHpA, C7), perfluorooctanoic acid (PFOA, C8), perfluorononanoic acid (PFNA, C9), perfluorodecanoic acid (PFDA, C10) and perfluoroundecanoic acid (PFUnDA, C11), significantly decreased BSP uptake by 27–55%, while coincubation with short- (C3–C6) and long-chain (C12–C14) PFCAs decreased the uptake only slightly. Dixon plotting suggested that PFOA, PFNA and PFDA competitively inhibited the BSP uptake with inhibition constant (K i ) values of 62.2 ± 1.3 μM, 35.3 ± 0.1 μM and 43.2 ± 0.3 μM, respectively. PFCAs with medium-chains could be substrates for OATPs, probably OATP2B1, which is the most abundantly expressed OATP isoform in Caco-2 cells.

Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression

“…Because Oatp1a4 was the most highly expressed transporter of the three, we targeted it with a relatively specific inhibitor, digoxin (10 μM) [ 60 ]. We used a mixture of 10 μM digoxin, 20 μM naringin, an Oatp1a5 inhibitor [ 61 ], and 30 μM bromsulfthalein, a broad Oatp inhibitor [ 62 ], to ensure all three Oatp1a members were inhibited. Compared to the no-inhibitor controls, the digoxin-only and inhibitor mixture groups showed 32.5 and 35.1% less PFOS retention (uptake).…”

Interactions of human drug transporters with chemical additives present in plastics: Potential consequences for toxicokinetics and health

“…Competitive or non-competitive interactions with drug binding sites on transporter proteins are likely involved, as proposed for drugs inhibiting transporters (Wigler and Patterson, 1993). The fact that BPA has been demonstrated to inhibit OAT3-mediated transport of estrone 3-sulfate in a competitive manner and that PFOA, perfluorononanoic acid (PFNA, 2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,9-heptadecafluorononanoic acid) and perfluorodecanoic acid (PFDA,2,2,3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10, competitively block OATP2B1-mediated uptake of sulfobromophthalein in Caco-2 cells (Kimura et al, 2020) fully supports this conclusion. BDEs probably also inhibit OATPs by competitive mechanisms because they are high affinity ligands for these SLCs (Pacyniak et al, 2010) (Table 5).…”

Role of ABCB1 and ABCB4 in renal and biliary excretion of perfluorooctanoic acid in mice

“…SLC22A11 encoding human OAT4 also transports PFOA in vitro [ 26 ], which may confer the placental barrier. Human intestinal Caco-2 cells show uptake of different PFASs, including PFOA, suggesting involvement of organic anion transporting polypeptides such as OATP2B1 [ 27 , 28 ]. In addition, Na + /taurocholate cotransporting polypeptide (SLC10A1) and apical sodium-dependent bile acid transporter (SLC10A2) mediate uptake of PFASs into hepatocytes [ 29 ].…”