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Research ArticleArticle

Characterization of Organic Anion Transporter 2 (SLC22A7): A Highly Efficient Transporter for Creatinine and Species-Dependent Renal Tubular Expression

Hong Shen, Tongtong Liu, Bridget L. Morse, Yue Zhao, Yueping Zhang, Xi Qiu, Cliff Chen, Anne C. Lewin, Xi-Tao Wang, Guowen Liu, Lisa J. Christopher, Punit Marathe and Yurong Lai
Drug Metabolism and Disposition July 2015, 43 (7) 984-993; DOI: https://doi.org/10.1124/dmd.114.062364
Hong Shen
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Tongtong Liu
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Bridget L. Morse
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Yue Zhao
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Yueping Zhang
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Xi Qiu
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Cliff Chen
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Anne C. Lewin
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Xi-Tao Wang
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Guowen Liu
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Lisa J. Christopher
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Punit Marathe
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Yurong Lai
Departments of Metabolism and Pharmacokinetics (H.S., T.L., B.L.M., Yuep.Z., X.Q., C.C., P.M., Y.L.), Bioanalytical Sciences (Y.Z., G.L.), Oncology Translational Research (A.C.L., X.-T.W.), and Biotransformation (L.J.C.), Bristol-Myers Squibb Research and Development, Princeton, New Jersey
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Abstract

The contribution of organic anion transporter OAT2 (SLC22A7) to the renal tubular secretion of creatinine and its exact localization in the kidney are reportedly controversial. In the present investigation, the transport of creatinine was assessed in human embryonic kidney (HEK) cells that stably expressed human OAT2 (OAT2-HEK) and isolated human renal proximal tubule cells (HRPTCs). The tubular localization of OAT2 in human, monkey, and rat kidney was characterized. The overexpression of OAT2 significantly enhanced the uptake of creatinine in OAT2-HEK cells. Under physiologic conditions (creatinine concentrations of 41.2 and 123.5 µM), the initial rate of OAT2-mediated creatinine transport was approximately 11-, 80-, and 80-fold higher than OCT2, multidrug and toxin extrusion protein (MATE)1, and MATE2K, respectively, resulting in approximately 37-, 1850-, and 80-fold increase of the intrinsic transport clearance when normalized to the transporter protein concentrations. Creatinine intracellular uptake and transcellular transport in HRPTCs were decreased in the presence of 50 µM bromosulfophthalein and 100 µM indomethacin, which inhibited OAT2 more potently than other known creatinine transporters, OCT2 and multidrug and toxin extrusion proteins MATE1 and MATE2K (IC50: 1.3 µM vs. > 100 µM and 2.1 µM vs. > 200 µM for bromosulfophthalein and indomethacin, respectively) Immunohistochemistry analysis showed that OAT2 protein was localized to both basolateral and apical membranes of human and cynomolgus monkey renal proximal tubules, but appeared only on the apical membrane of rat proximal tubules. Collectively, the findings revealed the important role of OAT2 in renal secretion and possible reabsorption of creatinine and suggested a molecular basis for potential species difference in the transporter handling of creatinine.

Footnotes

    • Received November 22, 2014.
    • Accepted April 22, 2015.
  • This work was supported by Bristol-Myers Squibb Company.

  • dx.doi.org/10.1124/dmd.114.062364.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (7)
Drug Metabolism and Disposition
Vol. 43, Issue 7
1 Jul 2015
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Research ArticleArticle

OAT2 Contributes to Renal Tubular Transport of Creatinine

Hong Shen, Tongtong Liu, Bridget L. Morse, Yue Zhao, Yueping Zhang, Xi Qiu, Cliff Chen, Anne C. Lewin, Xi-Tao Wang, Guowen Liu, Lisa J. Christopher, Punit Marathe and Yurong Lai
Drug Metabolism and Disposition July 1, 2015, 43 (7) 984-993; DOI: https://doi.org/10.1124/dmd.114.062364

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Research ArticleArticle

OAT2 Contributes to Renal Tubular Transport of Creatinine

Hong Shen, Tongtong Liu, Bridget L. Morse, Yue Zhao, Yueping Zhang, Xi Qiu, Cliff Chen, Anne C. Lewin, Xi-Tao Wang, Guowen Liu, Lisa J. Christopher, Punit Marathe and Yurong Lai
Drug Metabolism and Disposition July 1, 2015, 43 (7) 984-993; DOI: https://doi.org/10.1124/dmd.114.062364
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