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Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes

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Abstract

The objective of this study was to investigate the contributions of a sodium-dependent concentrative nucleoside transporter (CNT) 1 and an equilibrative nucleoside transporter (ENT) 1 to ribavirin uptake in human hepatocytes. The initial studies in oocytes expressing CNT1 and ENT1 showed increases in ribavirin uptake, indicating that ribavirin was a substrate for both CNT1 and ENT1. The CNT1- and ENT1-mediated ribavirin uptake showed concentration dependency with the following kinetics parameters: Km 26.3 μM and Vmax 426.2 fmol/min/oocyte for CNT1; Km 70.5 μM and Vmax 134.3 fmol/min/oocyte for ENT1. Ribavirin uptake clearance in six human hepatocytes ranged from 21.3 to 300.7 μL/min. Estimation of the contributions of CNT1 and ENT1 to the hepatic uptake of ribavirin by using a relative activity factor method indicated that the relative contribution of ENT1 to the ribavirin uptake was 82.8 ± 3.9 %. Real-time polymerase chain reaction analysis of CNT1 and ENT1 expressions in the hepatocytes showed that ENT1 mRNA expression was closely correlated with ribavirin uptake (R = 0.95, P = 0.003) while CNT1 was not. The findings indicated that ENT1 was the major transporter controlling the hepatic uptake of ribavirin.

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References

  • Baldwin, S.A., P.R. Beal, S.Y. Yao, A.E. King, C.E. Cass, and J.D. Young. 2004. The equilibrative nucleoside transporter family, SLC29. Pflugers Archiv 447: 735–743.

    Article  CAS  PubMed  Google Scholar 

  • Del Santo, B., G. Tarafa, A. Felipe, F.J. Casado, and M. Pastor-Anglada. 2001. Developmental regulation of the concentrative nucleoside transporters CNT1 and CNT2 in rat liver. Journal of Hepatology 34: 873–880.

    Article  PubMed  Google Scholar 

  • Govindarajan, R., C.J. Endres, D. Whittington, E. Lecluyse, M. Pastor-Anglada, C.M. Tse, and J.D. Unadkat. 2008. Expression and hepatobiliary transport characteristics of the concentrative and equilibrative nucleoside transporters in sandwich-cultured human hepatocytes. American Journal of Physiology. Gastrointestinal and Liver Physiology 295(3): G570–G580.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Gray, J.H., R.P. Owen, and K.M. Giacomini. 2004. The concentrative nucleoside transporter family, SLC28. Pflugers Archiv 447(5): 728–734.

    Article  CAS  PubMed  Google Scholar 

  • Hirano, M., K. Maeda, Y. Shitara, and Y. Sugiyama. 2004. Contribution of OATP2 (OATP1B1) and OATP8 (OATP1B3) to the hepatic uptake of pitavastatin in humans. Journal of Pharmacology and Experimental Therapeutics 311: 139–146.

    Article  CAS  PubMed  Google Scholar 

  • Jarvis, S.M., J.A. Thorn, and P. Glue. 1998. Ribavirin uptake by human erythrocytes and the involvement of nitrobenzylthioinosine-sensitive (es)-nucleoside transporters. British Journal of Pharmacology 123: 1587–1592.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kaneko, M., F. Hakuno, H. Kamei, D. Yamanaka, K. Chida, S. Minami, I.R. Coe, and S. Takahashi. 2014. Steroid hormones are novel nucleoside transport inhibitors by competition with nucleosides for their transporters. Biochemical and biophysical research communications 443(2): 505–510.

    Article  CAS  PubMed  Google Scholar 

  • Molina-Arcas, M., F.J. Casado, and M. Pastor-Anglada. 2009. Nucleoside transporter proteins. Current Vascular Pharmacology 7: 426–434.

    Article  CAS  PubMed  Google Scholar 

  • Moss, A.M., C.J. Endres, A. Ruiz-Garcia, D.S. Choi, and J.D. Unadkat. 2012. Role of the equilibrative and concentrative nucleoside transporters in the intestinal absorption of the nucleoside drug, ribavirin, in wild-type and Ent1(-/-) mice. Molecular Pharmaceutics 9: 2442–2449.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Parker, W.B. 2005. Metabolism and antiviral activity of ribavirin. Virus Research 107: 165–171.

    Article  CAS  PubMed  Google Scholar 

  • Podgorska, M., K. Kocbuch, and T. Pawelczyk. 2005. Recent advances in studies on biochemical and structural properties of equilibrative and concentrative nucleoside transporters. Acta Biochimica Polonica 52(4): 749–758.

    CAS  PubMed  Google Scholar 

  • Ulrich, C.M., K. Robien, and H.L. Mcleod. 2003. Cancer pharmacogenetics: Polymorphisms, pathways and beyond. Nature Reviews Cancer 3: 912–920.

    Article  CAS  PubMed  Google Scholar 

  • Valdes, R., F.J. Casado, and M. Pastor-Anglada. 2002. Cell-cycle-dependent regulation of CNT1, a concentrative nucleoside transporter involved in the uptake of cell-cycle-dependent nucleoside-derived anticancer drugs. Biochemical and biophysical research communications 296(3): 575–579.

    Article  CAS  PubMed  Google Scholar 

  • Valdes, R., M.A. Ortega, F.J. Casado, A. Felipe, A. Gil, A. Sanchez-Pozo, and M. Pastor-Anglada. 2000. Nutritional regulation of nucleoside transporter expression in rat small intestine. Gastroenterology 119: 1623–1630.

    Article  CAS  PubMed  Google Scholar 

  • Wong, A., R.A. Soo, W.P. Yong, and F. Innocenti. 2009. Clinical pharmacology and pharmacogenetics of gemcitabine. Drug Metabolism Reviews 41: 77–88.

    Article  CAS  PubMed  Google Scholar 

  • Yamamoto, T., K. Kuniki, Y. Takekuma, T. Hirano, K. Iseki, and M. Sugawara. 2007. Ribavirin uptake by cultured human choriocarcinoma (BeWo) cells and Xenopus laevis oocytes expressing recombinant plasma membrane human nucleoside transporters. European Journal of Pharmacology 557: 1–8.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This research was supported by Kyungpook National University Research Fund, 2012 (2013, 2014).

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The authors report no conflict of interest.

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Authors and Affiliations

  1. College of Pharmacy, Dankook University, 119 Dandaero, Cheonan, Chungnam, 330-714, Korea

    Min-Koo Choi

  2. College of Medicine and Pharmacogenomics Research Center, Inje University, 75 Bokgiro, Busan, 614-735, Korea

    Min-Hye Kim & Im-Sook Song

  3. College of Pharmacy, Inje University, 607 Obang-dong, Gimhae, Gyeongnam, 621-749, Korea

    Han-Joo Maeng

  4. College of Pharmacy and Research Institute of Pharmaceutical Sciences, Kyungpook National University, 80 Daehakro, Dae-gu, 702-701, Korea

    Im-Sook Song

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  1. Min-Koo Choi
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Correspondence to Im-Sook Song.

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Choi, MK., Kim, MH., Maeng, HJ. et al. Contribution of CNT1 and ENT1 to ribavirin uptake in human hepatocytes. Arch. Pharm. Res. 38, 904–913 (2015). https://doi.org/10.1007/s12272-014-0437-y

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  • DOI: https://doi.org/10.1007/s12272-014-0437-y

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