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Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir

  • Authors:
    • Yu‑Tian Liu
    • Wei Liu
    • Gang‑Yan Zhu
    • Fu‑Liang Wang
    • Qian Chen
  • View Affiliations / Copyright

    Affiliations: Department of Hand Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China, Department of Geriatrics, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 7113-7121
    |
    Published online on: March 19, 2018
       https://doi.org/10.3892/mmr.2018.8779
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Abstract

Multidrug resistance protein 4 (MRP4) is capable of transporting acyclic nucleotide phosphonates, but little is known about its role in lamivudine (LAM) and entecavir (ETV) transport. In the present study, the involvement of MRP4 in the transport of LAM and ETV was investigated through in vitro experiments. The cytotoxicity of three antiviral drugs and their activities against HBV as characterized in HepG2.4D14 [wild‑type hepatitis B virus (HBV)] and HepG2.A64 (ETV‑resistant HBV) cells. LAM, ETV and tenofovir (TFV) demonstrated a 50% effective concentration against HBV of 4.14±0.03, 0.13±0.02 and 3.24±0.01 µM in HepG2.4D14 cells and of 5.94±0.20, 6.28±0.07 and 11.43±0.09 µM in HepG2.A64 cells, respectively. After administering 3-([(3-(2-[7-chloro-2-quinolinyl]ethyl)phenyl]-[(3-dimethylamino-3-oxoporphyl)-thio)-methyl]-thio) propanoic acid (MK571), the intracellular concentrations of all three drugs were much lower than the extracellular drug concentrations in these two cell types, whereas the intracellular drug concentrations in wild‑type cells were higher than those in ETV‑resistant cells. Furthermore, the intracellular levels of LAM, ETV and TFV were enhanced and the extracellular concentrations were reduced by addition of MK571. Thus, MRP4 is mainly responsible for the efflux of LAM and ETV in hepatocyte cultures. These results may contribute to enhancing antiviral efficacy.
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1 

Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, Kumar A and Fridland A: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 5:1048–1051. 1999. View Article : Google Scholar : PubMed/NCBI

2 

Sodani K, Patel A, Kathawala RJ and Chen ZS: Multidrug resistance associated proteins in multidrug resistance. Chin J Cancer. 31:58–72. 2012. View Article : Google Scholar : PubMed/NCBI

3 

Imaoka T, Kusuhara H, Adachi M, Schuetz JD, Takeuchi K and Sugiyama Y: Functional involvement of multidrug resistance-associated protein 4 (MRP4/ABCC4) in the renal elimination of the antiviral drugs adefovir and tenofovir. Mol Pharmacol. 71:619–627. 2007. View Article : Google Scholar : PubMed/NCBI

4 

Fukuda Y, Takenaka K, Sparreboom A, Cheepala SB, Wu CP, Ekins S, Ambudkar SV and Schuetz JD: Human immunodeficiency virus protease inhibitors interact with ATP binding cassette transporter 4/multidrug resistance protein 4: A basis for unanticipated enhanced cytotoxicity. Mol Pharmacol. 84:361–371. 2013. View Article : Google Scholar : PubMed/NCBI

5 

Wen J, Luo J, Huang W, Tang J, Zhou H and Zhang W: The pharmacological and physiological role of multidrug-resistant protein 4. J Pharmacol Exp Ther. 354:358–375. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Takenaka K, Morgan JA, Scheffer GL, Adachi M, Stewart CF, Sun D, Leggas M, Ejendal KF, Hrycyna CA and Schuetz JD: Substrate overlap between Mrp4 and Abcg2/Bcrp affects purine analogue drug cytotoxicity and tissue distribution. Cancer Res. 67:6965–6972. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Ray AS, Cihlar T, Robinson KL, Tong L, Vela JE, Fuller MD, Wieman LM, Eisenberg EJ and Rhodes GR: Mechanism of active renal tubular efflux of tenofovir. Antimicrob Agents Chemother. 50:3297–3304. 2006. View Article : Google Scholar : PubMed/NCBI

8 

Mu L, Liu X, Li S, Tang F and Yu P: Determination of intracellular concentrations of nucleoside analogues and their phosphorylated metabolites. J Mol Pharm Org Process Res. 2:1122014.doi: 10.4172/2329-9053.1000112.

9 

Bushman LR, Kiser JJ, Rower JE, Klein B, Zheng JH, Ray ML and Anderson PL: Determination of nucleoside analog mono-, di-, and tri-phosphates in cellular matrix by solid phase extraction and ultra-sensitive LC-MS/MS detection. J Pharm Biomed Anal. 56:390–401. 2011. View Article : Google Scholar : PubMed/NCBI

10 

Zhang D, Fu Y, Gale JP, Aubry AF and Arnold ME: A sensitive method for the determination of entecavir at picogram per milliliter level in human plasma by solid phase extraction and high-pH LC-MS/MS. J Pharm Biomed Anal. 49:1027–1033. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Wang L, Liu Y, Liu W, et al: Establishment of three hepatoma cell lines stably replicating wild-type, entecavir-resistant or multidrug-resistant genotype C hepatitis B viruses. Hepatology. 54:1082A. 2011.

12 

Liu W, Song H, Chen Q, Xu C, Zhang W, Liu Y, Wang B, Xu D, Lu M, Yang D and Zheng X: Multidrug resistance protein 4 is a critical protein associated with the antiviral efficacy of nucleos(t)ide analogues. Liver Int. 36:1284–1294. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

14 

Fu X, Tan D, Dou X, Chen J and Wu J: A multi-center clinical study comparing Sansure Magb and CAP/CTM HBV tests in the quantitative detection of HBV DNA. J Infect Dev Ctries. 10:755–761. 2016. View Article : Google Scholar : PubMed/NCBI

15 

U.S. Department of Health and Human Services: Guidance for industry, . Bioanalytical method validation. https://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdfDecember 2–2015

16 

Hendrix CW, Chen BA, Guddera V, Hoesley C, Justman J, Nakabiito C, Salata R, Soto-Torres L, Patterson K, Minnis AM, et al: MTN-001: Randomized pharmacokinetic cross-over study comparing tenofovir vaginal gel and oral tablets in vaginal tissue and other compartments. PLoS One. 8:e550132013. View Article : Google Scholar : PubMed/NCBI

17 

Thompson CG, Cohen MS and Kashuba AD: Antiretroviral pharmacology in mucosal tissues. J Acquir Immune Defic Syndr. 63 Suppl 2:S240–S247. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Delaney WE IV, Ray AS, Yang H, Qi X, Xiong S, Zhu Y and Miller MD: Intracellular metabolism and in vitro activity of tenofovir against hepatitis B virus. Antimicrob Agents Chemother. 50:2471–2477. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Zhang X, Wang R, Piotrowski M, Zhang H and Leach KL: Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir. Toxicol In Vitro. 29:251–258. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Trufelli H, Palma P, Famiglini G and Cappiello A: An overview of matrix effects in liquid chromatography-mass spectrometry. Mass Spectrom Rev. 30:491–509. 2011. View Article : Google Scholar : PubMed/NCBI

21 

Gosetti F, Chiuminatto U, Zampieri D, Mazzucco E, Robotti E, Calabrese G, Gennaro MC and Marengo E: Determination of perfluorochemicals in biological, environmental and food samples by an automated on-line solid phase extraction ultra high performance liquid chromatography tandem mass spectrometry method. J Chromatogr A. 1217:7864–7872. 2010. View Article : Google Scholar : PubMed/NCBI

22 

Challa BR, Awen BZ, Chandu BR and Rihanaparveen S: LC-ESI-MS/MS method for the quantification of entecavir in human plasma and its application to bioequivalence study. J Chromatogr B Analyt Technol Biomed Life Sci. 879:769–776. 2011. View Article : Google Scholar : PubMed/NCBI

23 

Zhao FJ, Tang H, Zhang QH, Yang J, Davey AK and Wang JP: Salting-out homogeneous liquid-liquid extraction approach applied in sample pre-processing for the quantitative determination of entecavir in human plasma by LC-MS. J Chromatogr B Analyt Technol Biomed Life Sci. 881-882:119–125. 2012. View Article : Google Scholar : PubMed/NCBI

24 

Zacharis CK and Tzanavaras PD: Determination of bisphosphonate active pharmaceutical ingredients in pharmaceuticals and biological material: A review of analytical methods. J Pharm Biomed Anal. 48:483–496. 2008. View Article : Google Scholar : PubMed/NCBI

25 

Oeckl P and Ferger B: Simultaneous LC-MS/MS analysis of the biomarkers cAMP and cGMP in plasma, CSF and brain tissue. J Neurosci Methods. 203:338–343. 2012. View Article : Google Scholar : PubMed/NCBI

26 

Losa R, Sierra MI, Gion MO, Esteban E and Buesa JM: Simultaneous determination of gemcitabine di- and triphosphate in human blood mononuclear and cancer cells by RP-HPLC and UV detection. J Chromatogr B Analyt Technol Biomed Life Sci. 840:44–49. 2006. View Article : Google Scholar : PubMed/NCBI

27 

Huang J, Bathena SP, Csanaky IL and Alnouti Y: Simultaneous characterization of bile acids and their sulfate metabolites in mouse liver, plasma, bile, and urine using LC-MS/MS. J Pharm Biomed Anal. 55:1111–1119. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Bobeldijk I, Hekman M, de Vries-van der Weij J, Coulier L, Ramaker R, Kleemann R, Kooistra T, Rubingh C, Freidig A and Verheij E: Quantitative profiling of bile acids in biofluids and tissues based on accurate mass high resolution LC-FT-MS: Compound class targeting in a metabolomics workflow. J Chromatogr B Analyt Technol Biomed Life Sci. 871:306–313. 2008. View Article : Google Scholar : PubMed/NCBI

29 

Schuetz JD, Connelly MC, Sun D, Paibir SG, Flynn PM, Srinivas RV, Kumar A and Fridland A: MRP4: A previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 5:1048–1051. 1999. View Article : Google Scholar : PubMed/NCBI

30 

Rius M, Thon WF, Keppler D and Nies AT: Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. J Urol. 174:2409–2414. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Rius M, Nies AT, Hummel-Eisenbeiss J, Jedlitschky G and Keppler D: Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology. 38:374–384. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Sauna ZE, Nandigama K and Ambudkar SV: Multidrug resistance protein 4 (ABCC4)-mediated ATP hydrolysis: Effect of transport substrates and characterization of the post-hydrolysis transition state. J Biol Chem. 279:48855–48864. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Zelcer N, Reid G, Wielinga P, Kuil A, van der Heijden I, Schuetz JD and Borst P: Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochem J. 371:361–367. 2003. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Liu YT, Liu W, Zhu GY, Wang FL and Chen Q: Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir. Mol Med Rep 17: 7113-7121, 2018.
APA
Liu, Y., Liu, W., Zhu, G., Wang, F., & Chen, Q. (2018). Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir. Molecular Medicine Reports, 17, 7113-7121. https://doi.org/10.3892/mmr.2018.8779
MLA
Liu, Y., Liu, W., Zhu, G., Wang, F., Chen, Q."Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir". Molecular Medicine Reports 17.5 (2018): 7113-7121.
Chicago
Liu, Y., Liu, W., Zhu, G., Wang, F., Chen, Q."Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir". Molecular Medicine Reports 17, no. 5 (2018): 7113-7121. https://doi.org/10.3892/mmr.2018.8779
Copy and paste a formatted citation
x
Spandidos Publications style
Liu YT, Liu W, Zhu GY, Wang FL and Chen Q: Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir. Mol Med Rep 17: 7113-7121, 2018.
APA
Liu, Y., Liu, W., Zhu, G., Wang, F., & Chen, Q. (2018). Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir. Molecular Medicine Reports, 17, 7113-7121. https://doi.org/10.3892/mmr.2018.8779
MLA
Liu, Y., Liu, W., Zhu, G., Wang, F., Chen, Q."Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir". Molecular Medicine Reports 17.5 (2018): 7113-7121.
Chicago
Liu, Y., Liu, W., Zhu, G., Wang, F., Chen, Q."Involvement of multidrug resistance protein 4 in the hepatocyte efflux of lamivudine and entecavir". Molecular Medicine Reports 17, no. 5 (2018): 7113-7121. https://doi.org/10.3892/mmr.2018.8779
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