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Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates.
Toxicol Sci. 2010 Oct; 117(2):294-302.TS

Abstract

It has been hypothesized that human renal apical membrane transporters play a key role in human renal reabsorption of perfluorooctanoate (PFO), which contributes to the long half-life of PFO in humans. In the present study, PFO uptake kinetics of human organic anion-transporting polypeptide (OATP) 1A2, organic anion transporter (OAT) 4, and urate transporter 1 (URAT1) in stably transfected cell lines was investigated. OAT4 and URAT1, but not OATP1A2, were shown to mediate saturable PFO cellular uptake. OAT4-mediated PFO uptake was stimulated by a low extracellular pH, which was evidenced as a lower Michaelis constant (K(m)) at pH 6 (172.3 ± 45.9μM) than that at pH 7.4 (310.3 ± 30.2μM). URAT1-mediated PFO uptake was greatly enhanced by an outward Cl(-) gradient, and its K(m) value was determined to be 64.1 ± 30.5μM in the absence of extracellular Cl(-). The inhibition of OATP1A2- or OAT4-mediated estrone-3-sulfate uptake or URAT1-mediated urate uptake has been compared for linear perfluorocarboxylates (PFCs) with carbon chain lengths from 4 to 12. A clear chain length-dependent inhibition was observed, suggesting that PFCs in general are substrates of OAT4 and URAT1 but with different levels of affinities to the transporters depending on their chain length. Our results suggest that OAT4 and URAT1 are key transporters in renal reabsorption of PFCs in humans and, as a result, may contribute significantly to the long half-life of PFO in humans.

Authors+Show Affiliations

DuPont Haskell Global Centers for Health & Environmental Sciences, Newark, Delaware 19714, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

20639259

Citation

Yang, Ching-Hui, et al. "Characterization of Cellular Uptake of Perfluorooctanoate Via Organic Anion-transporting Polypeptide 1A2, Organic Anion Transporter 4, and Urate Transporter 1 for Their Potential Roles in Mediating Human Renal Reabsorption of Perfluorocarboxylates." Toxicological Sciences : an Official Journal of the Society of Toxicology, vol. 117, no. 2, 2010, pp. 294-302.
Yang CH, Glover KP, Han X. Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates. Toxicol Sci. 2010;117(2):294-302.
Yang, C. H., Glover, K. P., & Han, X. (2010). Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates. Toxicological Sciences : an Official Journal of the Society of Toxicology, 117(2), 294-302. https://doi.org/10.1093/toxsci/kfq219
Yang CH, Glover KP, Han X. Characterization of Cellular Uptake of Perfluorooctanoate Via Organic Anion-transporting Polypeptide 1A2, Organic Anion Transporter 4, and Urate Transporter 1 for Their Potential Roles in Mediating Human Renal Reabsorption of Perfluorocarboxylates. Toxicol Sci. 2010;117(2):294-302. PubMed PMID: 20639259.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates. AU - Yang,Ching-Hui, AU - Glover,Kyle P, AU - Han,Xing, Y1 - 2010/07/16/ PY - 2010/7/20/entrez PY - 2010/7/20/pubmed PY - 2011/1/5/medline SP - 294 EP - 302 JF - Toxicological sciences : an official journal of the Society of Toxicology JO - Toxicol Sci VL - 117 IS - 2 N2 - It has been hypothesized that human renal apical membrane transporters play a key role in human renal reabsorption of perfluorooctanoate (PFO), which contributes to the long half-life of PFO in humans. In the present study, PFO uptake kinetics of human organic anion-transporting polypeptide (OATP) 1A2, organic anion transporter (OAT) 4, and urate transporter 1 (URAT1) in stably transfected cell lines was investigated. OAT4 and URAT1, but not OATP1A2, were shown to mediate saturable PFO cellular uptake. OAT4-mediated PFO uptake was stimulated by a low extracellular pH, which was evidenced as a lower Michaelis constant (K(m)) at pH 6 (172.3 ± 45.9μM) than that at pH 7.4 (310.3 ± 30.2μM). URAT1-mediated PFO uptake was greatly enhanced by an outward Cl(-) gradient, and its K(m) value was determined to be 64.1 ± 30.5μM in the absence of extracellular Cl(-). The inhibition of OATP1A2- or OAT4-mediated estrone-3-sulfate uptake or URAT1-mediated urate uptake has been compared for linear perfluorocarboxylates (PFCs) with carbon chain lengths from 4 to 12. A clear chain length-dependent inhibition was observed, suggesting that PFCs in general are substrates of OAT4 and URAT1 but with different levels of affinities to the transporters depending on their chain length. Our results suggest that OAT4 and URAT1 are key transporters in renal reabsorption of PFCs in humans and, as a result, may contribute significantly to the long half-life of PFO in humans. SN - 1096-0929 UR - https://www.unboundmedicine.com/medline/citation/20639259/Characterization_of_cellular_uptake_of_perfluorooctanoate_via_organic_anion_transporting_polypeptide_1A2_organic_anion_transporter_4_and_urate_transporter_1_for_their_potential_roles_in_mediating_human_renal_reabsorption_of_perfluorocarboxylates_ L2 - https://academic.oup.com/toxsci/article-lookup/doi/10.1093/toxsci/kfq219 DB - PRIME DP - Unbound Medicine ER -