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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Hepatic Efflux Transporters of Organic Anions Using Double-Transfected Madin-Darby Canine Kidney II Cells Expressing Human Organic Anion-Transporting Polypeptide 1B1 (OATP1B1)/Multidrug Resistance-Associated Protein 2, OATP1B1/Multidrug Resistance 1, and OATP1B1/Breast Cancer Resistance Protein

Soichiro Matsushima, Kazuya Maeda, Chihiro Kondo, Masaru Hirano, Makoto Sasaki, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 2005, 314 (3) 1059-1067; DOI: https://doi.org/10.1124/jpet.105.085589
Soichiro Matsushima
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Kazuya Maeda
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Chihiro Kondo
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Masaru Hirano
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Makoto Sasaki
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Hiroshi Suzuki
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Yuichi Sugiyama
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Abstract

Until recently, it was generally believed that the transport of various organic anions across the bile canalicular membrane was mainly mediated by multidrug resistance-associated protein 2 (MRP2/ABCC2). However, a number of new reports have shown that some organic anions are also substrates of multidrug resistance 1 (MDR1/ABCB1) and/or breast cancer resistance protein (BCRP/ABCG2), implying MDR1 and BCRP could also be involved in the biliary excretion of organic anions in humans. In the present study, we constructed new double-transfected Madin-Darby canine kidney II (MDCKII) cells expressing organic anion-transporting polypeptide 1B1 (OATP1B1)/MDR1 and OATP1B1/BCRP, and we investigated the transcellular transport of four kinds of organic anions, estradiol-17β-d-glucuronide (EG), estrone-3-sulfate (ES), pravastatin (PRA), and cerivastatin (CER), to identify which efflux transporters mediate the biliary excretion of compounds using double-transfected cells. We observed the vectorial transport of EG and ES in all the double transfectants. MRP2 showed the highest efflux clearance of EG among these efflux transporters, whereas BCRP-mediated clearance of ES was the highest in these double transfectants. In addition, two kinds of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, CER and PRA, were also substrates of all these efflux transporters. The rank order of the efflux clearance of PRA mediated by each transporter was the same as that of EG, whereas the contribution of MDR1 to the efflux of CER was relatively greater than for PRA. This experimental system is very useful for identifying which transporters are involved in the biliary excretion of organic anions that cannot easily penetrate the plasma membrane.

Footnotes

  • This study was supported by Health and Labor Sciences Research grants from the Ministry of Health, Labor, and Welfare for the Research on Advanced Medical Technology and by Grant-in-Aid for Young Scientists B (15790087) from the Ministry of Education, Culture, Sports, Science, and Technology.

  • doi:10.1124/jpet.105.085589.

  • ABBREVIATIONS: ABC, ATP-binding cassette; MRP, multidrug resistance-associated protein; EHBR, Eisai hyperbilirubinemic rats; MDR, multidrug resistance; EG, estradiol-17β-d-glucuronide; E3040, 6-hydroxy-5,7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole; BCRP, breast cancer resistance protein; MDCK, Madin-Darby canine kidney; OATP, organic anion-transporting polypeptide; PRA, pravastatin; HMG, 3-hydroxy-3-methylglutaryl; ES, estrone-3-sulfate; CER, cerivastatin; PBS, phosphate-buffered saline; TTBS, Tris-buffered saline with 0.05% Tween 20; PS, permeability surface product.

    • Received February 28, 2005.
    • Accepted May 17, 2005.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Identification of the Hepatic Efflux Transporters of Organic Anions Using Double-Transfected Madin-Darby Canine Kidney II Cells Expressing Human Organic Anion-Transporting Polypeptide 1B1 (OATP1B1)/Multidrug Resistance-Associated Protein 2, OATP1B1/Multi…
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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Hepatic Efflux Transporters of Organic Anions Using Double-Transfected Madin-Darby Canine Kidney II Cells Expressing Human Organic Anion-Transporting Polypeptide 1B1 (OATP1B1)/Multidrug Resistance-Associated Protein 2, OATP1B1/Multidrug Resistance 1, and OATP1B1/Breast Cancer Resistance Protein

Soichiro Matsushima, Kazuya Maeda, Chihiro Kondo, Masaru Hirano, Makoto Sasaki, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 1, 2005, 314 (3) 1059-1067; DOI: https://doi.org/10.1124/jpet.105.085589

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Research ArticleABSORPTION, DISTRIBUTION, METABOLISM, AND EXCRETION

Identification of the Hepatic Efflux Transporters of Organic Anions Using Double-Transfected Madin-Darby Canine Kidney II Cells Expressing Human Organic Anion-Transporting Polypeptide 1B1 (OATP1B1)/Multidrug Resistance-Associated Protein 2, OATP1B1/Multidrug Resistance 1, and OATP1B1/Breast Cancer Resistance Protein

Soichiro Matsushima, Kazuya Maeda, Chihiro Kondo, Masaru Hirano, Makoto Sasaki, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics September 1, 2005, 314 (3) 1059-1067; DOI: https://doi.org/10.1124/jpet.105.085589
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