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Research ArticleArticle

Multidrug Resistance-Associated Protein 4 (MRP4/ABCC4) Controls Efflux Transport of Hesperetin Sulfates in Sulfotransferase 1A3–Overexpressing Human Embryonic Kidney 293 Cells

Hua Sun, Xiao Wang, Xiaotong Zhou, Danyi Lu, Zhiguo Ma and Baojian Wu
Drug Metabolism and Disposition October 2015, 43 (10) 1430-1440; DOI: https://doi.org/10.1124/dmd.115.065953
Hua Sun
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Xiao Wang
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Xiaotong Zhou
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Danyi Lu
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Zhiguo Ma
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Baojian Wu
Division of Pharmaceutics, College of Pharmacy (H.S., X.Z., D.L., Z.M., B.W.) and Guangzhou Jinan Biomedicine Research and Development Center, Jinan University, Guangzhou, China (X.W.)
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Abstract

Sulfonation is an important metabolic pathway for hesperetin. However, the mechanisms for the cellular disposition of hesperetin and its sulfate metabolites are not fully established. In this study, disposition of hesperetin via the sulfonation pathway was investigated using human embryonic kidney (HEK) 293 cells overexpressing sulfotransferase 1A3. Two monosulfates, hesperetin-3′-O-sulfate (H-3′-S) and hesperetin-7-O-sulfate (H-7-S), were rapidly generated and excreted into the extracellular compartment upon incubation of the cells with hesperetin. Regiospecific sulfonation of hesperetin by the cell lysate followed the substrate inhibition kinetics (Vmax = 0.66 nmol/min per mg, Km = 12.9 μM, and Ksi= 58.1 μM for H-3′-S; Vmax = 0.29 nmol/min per mg, Km = 14.8 μM, and Ksi= 49.1 μM for H-7-S). The pan–multidrug resistance-associated protein (MRP) inhibitor MK-571 at 20 μM essentially abolished cellular excretion of both H-3′-S and H-7-S (the excretion activities were only 6% of the control), whereas the breast cancer resistance protein–selective inhibitor Ko143 had no effects on sulfate excretion. In addition, knockdown of MRP4 led to a substantial reduction (>47.1%; P < 0.01) in sulfate excretion. Further, H-3′-S and H-7-S were good substrates for transport by MRP4 according to the vesicular transport assay. Moreover, sulfonation of hesperetin and excretion of its metabolites were well characterized by a two-compartment pharmacokinetic model that integrated drug uptake and sulfonation with MRP4-mediated sulfate excretion. In conclusion, the exporter MRP4 controlled efflux transport of hesperetin sulfates in HEK293 cells. Due to significant expression in various organs/tissues (including the liver and kidney), MRP4 should be a determining factor for the elimination and body distribution of hesperetin sulfates.

Footnotes

    • Received June 15, 2015.
    • Accepted July 29, 2015.
  • H.S. and X.W. contributed equally to this work

  • This work was supported by the Young Scientist Special Projects in Biotechnological Pharmaceutical Field of 863 Program [Grant 2015AA020916] and the National Natural Science Foundation of China [Grant 81373496].

  • dx.doi.org/10.1124/dmd.115.065953.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 43 (10)
Drug Metabolism and Disposition
Vol. 43, Issue 10
1 Oct 2015
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Research ArticleArticle

Transport of Hesperetin Sulfates by MRP4

Hua Sun, Xiao Wang, Xiaotong Zhou, Danyi Lu, Zhiguo Ma and Baojian Wu
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1430-1440; DOI: https://doi.org/10.1124/dmd.115.065953

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Research ArticleArticle

Transport of Hesperetin Sulfates by MRP4

Hua Sun, Xiao Wang, Xiaotong Zhou, Danyi Lu, Zhiguo Ma and Baojian Wu
Drug Metabolism and Disposition October 1, 2015, 43 (10) 1430-1440; DOI: https://doi.org/10.1124/dmd.115.065953
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