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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions — Short Communication

Multidrug Resistance–Associated Protein 3 Is Responsible for the Efflux Transport of Curcumin Glucuronide from Hepatocytes to the Blood

Yu-Meng Jia, Ting Zhu, Huan Zhou, Jin-Zi Ji, Ting Tai and Hong-Guang Xie
Drug Metabolism and Disposition October 2020, 48 (10) 966-971; DOI: https://doi.org/10.1124/dmd.119.089193
Yu-Meng Jia
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Ting Zhu
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Huan Zhou
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Jin-Zi Ji
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Ting Tai
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Hong-Guang Xie
Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, People’s Republic of China (Y.-M.J., J.-Z.J., T.T., H.-G.X.); Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People’s Republic of China (Y.-M.J., T.Z., H.Z., H.-G.X.); and Department of Clinical Pharmacy, Nanjing Medical University School of Pharmacy, Nanjing, People’s Republic of China (H.-G.X.)
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Abstract

Curcumin, a major polyphenol present in turmeric, is predominantly converted to curcumin-O-glucuronide (COG) in enterocytes and hepatocytes via glucuronidation. COG is a principal metabolite of curcumin in plasma and feces. It appears that the efflux transport of the glucuronide conjugates of many compounds is mediated largely by multidrug resistance–associated protein (MRP) 3, the gene product of the ATP-binding cassette, subfamily C, member 3. However, it is currently unknown whether this was the case with COG. In this study, Mrp3 knockout (KO) and wild-type (WT) mice were used to evaluate the pharmacokinetics profiles of COG, the liver-to-plasma ratio of COG, and the COG-to-curcumin ratio in plasma, respectively. The ATP-dependent uptake of COG into recombinant human MRP3 inside-out membrane vesicles was measured for further identification, with estradiol-17β-d-glucuronide used in parallel as the positive control. Results showed that plasma COG concentrations were extremely low in KO mice compared with WT mice, that the liver-to-plasma ratios of COG were 8-fold greater in KO mice than in WT mice, and that the ATP-dependent uptake of COG at 1 or 10 μM was 5.0- and 3.1-fold greater in the presence of ATP than in the presence of AMP, respectively. No significant differences in the Abcc2 and Abcg2 mRNA expression levels were seen between Mrp3 KO and WT mice. We conclude that Mrp3 is identified to be the main efflux transporter responsible for the transport of COG from hepatocytes into the blood.

SIGNIFICANCE STATEMENT This study was designed to determine whether multidrug resistance–associated protein (Mrp) 3 could be responsible for the efflux transport of curcumin-O-glucuronide (COG), a major metabolite of curcumin present in plasma and feces, from hepatocytes into the blood using Mrp3 knockout mice. In this study, COG was identified as a typical Mrp3 substrate. Results suggest that herb-drug interactions would occur in patients concomitantly taking curcumin and either an MRP3 substrate/inhibitor or a drug that is predominantly glucuronidated by UDP-glucuronosyltransferases.

Footnotes

    • Received August 27, 2019.
    • Accepted December 18, 2019.
  • This work was supported in part by the National Natural Science Foundation of China [Grant 81473286 to H.-G.X.] and Nanjing First Hospital [Grant 31010300010339 to H.-G.X.]. H.-G.X. is the recipient of the Distinguished Medical Experts of the Province of Jiangsu, China.

  • https://doi.org/10.1124/dmd.119.089193.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 48 (10)
Drug Metabolism and Disposition
Vol. 48, Issue 10
1 Oct 2020
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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions — Short Communication

MRP3 Transports Curcumin Glucuronide

Yu-Meng Jia, Ting Zhu, Huan Zhou, Jin-Zi Ji, Ting Tai and Hong-Guang Xie
Drug Metabolism and Disposition October 1, 2020, 48 (10) 966-971; DOI: https://doi.org/10.1124/dmd.119.089193

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Research ArticleSpecial Section on Natural Products: Experimental Approaches to Elucidate Disposition Mechanisms and Predict Pharmacokinetic Drug Interactions — Short Communication

MRP3 Transports Curcumin Glucuronide

Yu-Meng Jia, Ting Zhu, Huan Zhou, Jin-Zi Ji, Ting Tai and Hong-Guang Xie
Drug Metabolism and Disposition October 1, 2020, 48 (10) 966-971; DOI: https://doi.org/10.1124/dmd.119.089193
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