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Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice

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Abstract

The MRP family is composed of nine transporters, at least eight of which are lipophilic anion transporters that are capable of conferring resistance to various anticancer agents. Recently, mice with gene disruptions in Mrp2, Mrp3 and Mrp4 have been developed. This review will discuss insights into the physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 afforded by investigations of these new mouse models.

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Abbreviations

CDF:

5-(and 6)-carboxy-2′,7′dichlorofluorescein

DBSP:

dibromosulphthalein

HPMPC:

1′-(3′-hydroxy-2-phosphonylmethoxypropyl)cytosine

MRP:

multidrug resistance protein

PMEA:

9′-(2′-phosphonylmethoxyethyl)-adenine

PMPA:

9′-(2-phosphonomethoxypropyl)adenine

References

  1. Kruh, G. D., & Belinsky, M. G. (2003). The MRP family of drug efflux pumps. Oncogene, 22, 7537–7552.

    Article  PubMed  CAS  Google Scholar 

  2. Borst, P., & Elferink, R. O. (2002). Mammalian ABC transporters in health and disease. Annu Rev Biochem, 71, 537–592.

    Article  PubMed  CAS  Google Scholar 

  3. Deeley, R. G., Westlake, C., & Cole, S. P. (2006). Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiological Reviews, 86, 849–899.

    Article  PubMed  CAS  Google Scholar 

  4. Nies, A. T., & Keppler, D. (2006). The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Archiv.

  5. Borst, P., de Wolf, C., & van de Wetering, K. (2006). Multidrug resistance-associated proteins 3, 4, and 5. Pflugers Archiv.

  6. Kruh, G. D., Guo, Y., Hopper-Borge, E., Belinsky, M. G., & Chen, Z. S. (2006). ABCC10, ABCC11, and ABCC12. Pflugers Archiv.

  7. Lorico, A., Rappa, G., Finch, R. A., Yang, D., Flavell, R. A., & Sartorelli, A. C. (1997). Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Research, 57, 5238–5242.

    PubMed  CAS  Google Scholar 

  8. Wijnholds, J., Evers, R., van Leusden, M. R., Mol, C. A., Zaman, G. J., Mayer, U., et al. (1997). Increased sensitivity to anticancer drugs and decreased inflammatory response in mice lacking the multidrug resistance-associated protein. Natural Medicines, 3, 1275–1279.

    Article  CAS  Google Scholar 

  9. Johnson, D. R., Finch, R. A., Lin, Z. P., Zeiss, C. J., & Sartorelli, A. C. (2001). The pharmacological phenotype of combined multidrug-resistance mdr1a/1b- and mrp1-deficient mice. Cancer Research, 61, 1469–1476.

    PubMed  CAS  Google Scholar 

  10. Wijnholds, J., Scheffer, G. L., van der Valk, M., van der Valk, P., Beijnen, J. H., Scheper, R. J., et al. (1998). Multidrug resistance protein 1 protects the oropharyngeal mucosal layer and the testicular tubules against drug-induced damage. Journal of Experimental Medicine, 188, 797–808.

    Article  PubMed  CAS  Google Scholar 

  11. Wijnholds, J., deLange, E. C, Scheffer, G. L., van den Berg, D. J., Mol, C. A., van der Valk, M., et al. (2000). Multidrug resistance protein 1 protects the choroid plexus epithelium and contributes to the blood-cerebrospinal fluid barrier. Journal of Clinical Investigation, 105, 279–285.

    Article  PubMed  CAS  Google Scholar 

  12. Robbiani, D. F., Finch, R. A., Jager, D., Muller, W. A., Sartorelli, A. C., & Randolph, G. J. (2000). The leukotriene C(4) transporter MRP1 regulates CCL19 (MIP-3beta, ELC)- dependent mobilization of dendritic cells to lymph nodes. Cell, 103, 757–768.

    Article  PubMed  CAS  Google Scholar 

  13. Schultz, M. J., Wijnholds, J., Peppelenbosch, M. P., Vervoordeldonk, M. J., Speelman, P., van Deventer, S. J., et al. (2001). Mice lacking the multidrug resistance protein 1 are resistant to Streptococcus pneumoniae-induced pneumonia. Journal of Immunology, 166, 4059–4064.

    CAS  Google Scholar 

  14. Klement, J. F., Matsuzaki, Y., Jiang, Q. J., Terlizzi, J., Choi, H. Y., Fujimoto, N., et al. (2005). Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues. Molecular and Cellular Biology, 25, 8299–8310.

    Article  PubMed  CAS  Google Scholar 

  15. Gorgels, T. G, Hu, X., Scheffer, G. L., van der Wal, A. C., Toonstra, J., de Jong, P. T., et al. (2005). Disruption of Abcc6 in the mouse: Novel insight in the pathogenesis of pseudoxanthoma elasticum. Human Molecular Genetics, 14, 1763–1773.

    Article  PubMed  CAS  Google Scholar 

  16. Jiang, Q., & Uitto, J. (2006). Pseudoxanthoma elasticum: A metabolic disease? Journal of Investigative Dermatology, 126, 1440–1441.

    Article  PubMed  CAS  Google Scholar 

  17. Gerk, P. M., & Vore, M. (2002). Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. Journal of Pharmacology and Experimental Therapeutics, 302, 407–415.

    Article  PubMed  CAS  Google Scholar 

  18. Jansen, P. L., Peters, W. H., & Lamers, W. H. (1985). Hereditary chronic conjugated hyperbilirubinemia in mutant rats caused by defective hepatic anion transport. Hepatology, 5, 573–579.

    Article  PubMed  CAS  Google Scholar 

  19. Hosokawa, S., Tagaya, O., Mikami, T., Nozaki, Y., Kawaguchi, A., Yamatsu, K., et al. (1992). A new rat mutant with chronic conjugated hyperbilirubinemia and renal glomerular lesions. Laboratory Animal Science, 42, 27–34.

    PubMed  CAS  Google Scholar 

  20. Masuda, M., I’izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni’inuma, K., et al. (1997). Methotrexate is excreted into the bile by canalicular multispecific organic anion transporter in rats. Cancer Research, 57, 3506–3510.

    PubMed  CAS  Google Scholar 

  21. Chu, X. Y., Kato, Y., Niinuma, K., Sudo, K. I., Hakusui, H., & Sugiyama, Y. (1997). Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. Journal of Pharmacology and Experimental Therapeutics, 281, 304–314.

    PubMed  CAS  Google Scholar 

  22. Chu, X. Y., Strauss, J. R., Mariano, M. A., Li, J., Newton, D. J., Cai, X., et al. (2006). Characterization of mice lacking the multidrug resistance protein MRP2 (ABCC2). Journal of Pharmacology and Experimental Therapeutics, 317, 579–589.

    Article  PubMed  CAS  Google Scholar 

  23. Vlaming, M. L., Mohrmann, K., Wagenaar, E., de Waart, D. R., Elferink, R. P., Lagas, J. S., et al. (2006). Carcinogen and anticancer drug transport by Mrp2 in vivo: Studies using Mrp2 (Abcc2) knockout mice. Journal of Pharmacology and Experimental Therapeutics, 318, 319–327.

    Article  PubMed  CAS  Google Scholar 

  24. Nezasa, K., Tian, X., Zamek-Gliszczynski, M. J., Patel, N. J., Raub, T. J., & Brouwer, K. L. (2006). Altered hepatobiliary disposition of 5 (and 6)-carboxy-2′,7′-dichlorofluorescein in Abcg2 (Bcrp1) and Abcc2 (Mrp2) knockout mice. Drug Metabolism and Disposition, 34, 718–723.

    Article  PubMed  CAS  Google Scholar 

  25. Zamek-Gliszczynski, M. J., Xiong, H., Patel, N. J., Turncliff, R. Z., Pollack, G. M., & Brouwer, K. L. (2003). Pharmacokinetics of 5 (and 6)-carboxy-2′,7′-dichlorofluorescein and its diacetate promoiety in the liver. Journal of Pharmacology and Experimental Therapeutics, 304, 801–809.

    Article  PubMed  CAS  Google Scholar 

  26. Hirohashi, T., Suzuki, H., Ito, K., Ogawa, K., Kume, K., Shimizu, T., et al. (1998). Hepatic expression of multidrug resistance-associated protein-like proteins maintained in eisai hyperbilirubinemic rats. Molecular Pharmacology, 53, 1068–1075.

    PubMed  CAS  Google Scholar 

  27. Konig, J., Rost, D., Cui, Y., & Keppler, D. (1999). Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology, 29, 1156–1163.

    Article  PubMed  CAS  Google Scholar 

  28. Chen, C., Slitt, A. L., Dieter, M. Z., Tanaka, Y., Scheffer, G. L., & Klaassen, C. D. (2005). Up-regulation of Mrp4 expression in kidney of Mrp2-deficient TR rats. Biochemical Pharmacology, 70, 1088–1095.

    Article  PubMed  CAS  Google Scholar 

  29. van Aubel, R. A., Smeets, P. H., Peters, J. G., Bindels, R. J., & Russel, F. G. (2002). The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules: putative efflux pump for urinary cAMP and cGMP. Journal of the American Society of Nephrology, 13, 595–603.

    PubMed  Google Scholar 

  30. Zamek-Gliszczynski, M. J., Nezasa, K., Tian, X., Kalvass, J. C., Patel, N. J., Raub, T. J., et al. (2006). The important role of bcrp (abcg2) in the biliary excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in mice. Molecular Pharmacology, 70, 2127–2133.

    Article  PubMed  CAS  Google Scholar 

  31. Lagas, J. S., Vlaming, M. L., van Tellingen, O., Wagenaar, E., Jansen, R. S., Rosing, H., et al. (2006). Multidrug resistance protein 2 is an important determinant of paclitaxel pharmacokinetics. Clinical Cancer Research, 12, 6125–6132.

    Article  PubMed  CAS  Google Scholar 

  32. Kool, M., van der Linden, M., de Haas, M., Scheffer, G. L., de Vree, J. M., Smith, A. J., et al. (1999). MRP3, an organic anion transporter able to transport anti-cancer drugs. Proceedings of the National Academy of Sciences of the United States of America, 96, 6914–6919.

    Article  PubMed  CAS  Google Scholar 

  33. Zeng, H., Bain, L. J. Belinsky, M. G., & Kruh, G. D. (1999). Expression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents. Cancer Research 59, 5964–5967.

    PubMed  CAS  Google Scholar 

  34. Zeng, H., Chen, Z.-S., Belinsky, M. G., Rea, P. A., & Kruh, G. D. (2001). Transport of methotrexate (MTX) and folates by multidrug resistance protein (MRP) 3 and MRP1: Effect of polyglutamylation on MTX transport. Cancer Research, 61, 7225–7232.

    PubMed  CAS  Google Scholar 

  35. Hirohashi, T., Suzuki, H., & Sugiyama, Y. (1999). Characterization of the transport properties of cloned rat multidrug resistance-associated protein 3 (MRP3). Journal of Biological Chemistry, 274, 15181–15185.

    Article  PubMed  CAS  Google Scholar 

  36. Hirohashi, T., Suzuki, H., Takikawa, H., & Sugiyama, Y. (2000). ATP-dependent transport of bile salts by rat multidrug resistance-associated protein 3 (Mrp3). Journal of Biological Chemistry, 275, 2905–2910.

    Article  PubMed  CAS  Google Scholar 

  37. Zeng, H., Liu, G., Rea, P. A., & Kruh, G. D. (2000). Transport of amphipathic anions by human multidrug resistance protein 3. Cancer Research, 60, 4779–4784.

    PubMed  CAS  Google Scholar 

  38. Scheffer, G. L., Kool, M., de Haas, M., de Vree, J. M., Pijnenborg, A. C., Bosman, D. K., et al. (2002). Tissue distribution and induction of human multidrug resistant protein 3. Laboratory Investigation, 82, 193–201.

    PubMed  CAS  Google Scholar 

  39. Belinsky, M. G., Bain, L. J., Balsara, B. B., Testa, J. R., & Kruh, G. D. (1998). Characterization of MOAT-C and MOAT-D, new members of the MRP/cMOAT subfamily of transporter proteins. Journal of the National Cancer Institute, 90, 1735–1741.

    Article  PubMed  CAS  Google Scholar 

  40. Donner, M. G., & Keppler, D. (2001). Up-regulation of basolateral multidrug resistance protein 3 (Mrp3) in cholestatic rat liver. Hepatology, 34, 351–359.

    Article  PubMed  CAS  Google Scholar 

  41. Soroka, C. J., Lee, J. M., Azzaroli, F., & Boyer, J. L. (2001). Cellular localization and up-regulation of multidrug resistance- associated protein 3 in hepatocytes and cholangiocytes during obstructive cholestasis in rat liver. Hepatology, 33, 783–791.

    Article  PubMed  CAS  Google Scholar 

  42. Benderra, Z., Faussat, A. M., Sayada, L., Perrot, J. Y., Tang, R., Chaoui, D., et al. (2005). MRP3, BCRP, and P-glycoprotein activities are prognostic factors in adult acute myeloid leukemia. Clinical Cancer Research, 11, 7764–7772.

    Article  PubMed  CAS  Google Scholar 

  43. Konig, J., Hartel, M., Nies, A. T., Martignoni, M. E., Guo, J., Buchler, M. W., et al. (2005). Expression and localization of human multidrug resistance protein (ABCC) family members in pancreatic carcinoma. International Journal of Cancer, 115, 359–367.

    Article  CAS  Google Scholar 

  44. Oda, Y., Saito, T., Tateishi, N., Ohishi, Y., Tamiya, S., Yamamoto, H., et al. (2005). ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas. International Journal of Cancer, 114, 854–862.

    Article  CAS  Google Scholar 

  45. Plasschaert, S. L., de Bont, E. S, Boezen, M., vander Kolk, D. M., Daenen, S. M., Faber, K. N., et al. (2005). Expression of multidrug resistance-associated proteins predicts prognosis in childhood and adult acute lymphoblastic leukemia. Clinical Cancer Research, 11, 8661–8668.

    Article  PubMed  CAS  Google Scholar 

  46. Steinbach, D., Wittig, S., Cario, G., Viehmann, S., Mueller, A., Gruhn, B., et al. (2003). The multidrug resistance-associated protein 3 (MRP3) is associated with a poor outcome in childhood ALL and may account for the worse prognosis in male patients and T-cell immunophenotype. Blood, 102, 4493–4498.

    Article  PubMed  CAS  Google Scholar 

  47. Belinsky, M. G., Dawson, P. A., Shchaveleva, I., Bain, L. J., Wang, R., Ling, V., et al. (2005). Analysis of the in vivo functions of Mrp3. Molecular Pharmacology, 68, 160–168.

    PubMed  CAS  Google Scholar 

  48. Zelcer, N., Wetering, K. V., Waart, R. D., Scheffer, G. L., Marschall, H. U., Wielinga, P. R., et al. (2005). Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides. Journal of Hepatology.

  49. Dawson, P. A., Hubbert, M., Haywood, J., Craddock, A. L., Zerangue, N., Christian, W. V., et al. (2005). The heteromeric organic solute transporter alpha-beta, Ostalpha-Ostbeta, is an ileal basolateral bile acid transporter. Journal of Biological Chemistry, 280, 6960–6968.

    Article  PubMed  CAS  Google Scholar 

  50. Ballatori, N., Christian, W. V., Lee, J. Y., Dawson, P.A., Soroka, C. J., Boyer, J. L., et al. (2005). OSTalpha-OSTbeta: A major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology, 42, 1270–1279.

    Article  PubMed  CAS  Google Scholar 

  51. Zelcer, N., van de Wetering, K., Hillebrand, M., Sarton, E., Kuil, A., & Wielinga, P. R., et al. (2005). Mice lacking multidrug resistance protein 3 show altered morphine pharmacokinetics and morphine-6-glucuronide antinociception. Proceedings of the National Academy of Sciences of the United States of America, 102, 7274–7279.

    Article  PubMed  CAS  Google Scholar 

  52. Manautou, J. E., de Waart, D. R., Kunne, C., Zelcer, N., Goedken, M., Borst, P., et al. (2005). Altered disposition of acetaminophen in mice with a disruption of the Mrp3 gene. Hepatology, 42, 1091–1098.

    Article  PubMed  CAS  Google Scholar 

  53. Zamek-Gliszczynski, M. J., Nezasa, K. I., Tian, X., Bridges, A. S., Lee, K., Belinsky, M. G., et al. (2006). Evaluation of the role of Mrp3 and Mrp4 in hepatic basolateral excretion of sulfate and glucuronide metabolites of acetaminophen, 4-methylumbelliferone, and harmol in Abcc3(−/−) and Abcc4(−/−) mice. Journal of Pharmacology and Experimental Therapeutics.

  54. Zelcer, N., Saeki, T., Reid, G., Beijnen, J. H., & Borst, P. (2001). Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). Journal of Biological Chemistry, 276, 46400–46407.

    Article  PubMed  CAS  Google Scholar 

  55. Bohan, A., Chen, W. S., Denson, L. A., Held, M. A., & Boyer, J. L. (2003). Tumor necrosis factor alpha-dependent up-regulation of Lrh-1 and Mrp3(Abcc3) reduces liver injury in obstructive cholestasis. Journal of Biological Chemistry, 278, 36688–36698.

    Article  PubMed  CAS  Google Scholar 

  56. Mennone, A., Soroka, C. J., Cai, S. Y., Harry, K., Adachi, M., Hagey, L., et al. (2006). Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis. Hepatology, 43, 1013–1021.

    Article  PubMed  CAS  Google Scholar 

  57. Lee, K., Belinsky, M. G., Bell, D. W., Testa, J. R., & Kruh, G. D. (1998). Isolation of MOAT-B, a widely expressed multidrug resistance-associated protein/canalicular multispecific organic anion transporter-related transporter. Cancer Research, 58, 2741–2747.

    PubMed  CAS  Google Scholar 

  58. Chen, Z.-S., Lee, K., & Kruh, G. D. (2001). Transport of cyclic nucleotides and estradiol 17-β-d-glucuronide by multidrug resistance protein 4. Resistance to 6-mercaptopurine and 6-thioguanine. Journal of Biological Chemistry, 276, 33747–33754.

    Article  PubMed  CAS  Google Scholar 

  59. Chen, Z.-S., Lee, K., Walther, S., Blanchard Raftogianis, R., Kuwano, M., Zeng, H., et al. (2002). Analysis of methotrexate and folate transport by multidrug resistance protein 4: MRP4 is a component of the methotrexate efflux system. Cancer Research, 62, 3144–3150.

    PubMed  CAS  Google Scholar 

  60. Jedlitschky, G., Burchell, B., & Keppler, D. (2000). The multidrug resistance protein 5 functions as an ATP-dependent export pump for cyclic nucleotides. Journal of Biological Chemistry, 275, 30069–30074.

    Article  PubMed  CAS  Google Scholar 

  61. Wielinga, P. R., Van Der Heijden, I., Reid, G., Beijnen, J. H., Wijnholds, J., & Borst, P. (2003). Characterization of the MRP4-and MRP5-mediated transport of cyclic nucleotides from intact cells. Journal of Biological Chemistry 278, 17664–17671.

    Article  PubMed  CAS  Google Scholar 

  62. Chen, Z. S., Guo, Y., Belinsky, M. G., Kotova, E., & Kruh, G. D. (2005). Transport of bile acids, sulfated steroids, estradiol 17-beta-d-glucuronide, and leukotriene C4 by human multidrug resistance protein 8 (ABCC11). Molecular Pharmacology, 67, 545–557.

    Article  PubMed  CAS  Google Scholar 

  63. Guo, Y., Kotova, E., Chen, Z.-S., Lee, K., Hopper-Borge, E., Belinsky, M. G., et al. (2003). MRP8, ATP-binding cassette C11 (ABCC11), is a cyclic nucleotide efflux pump and a resistance factor for fluoropyrimidines, 2′,3′-dideoxycytidine and 9′-(2′-phosphonylmethoxyethyl)adenine. Journal of Biological Chemistry, 278, 29509–29514.

    Article  PubMed  CAS  Google Scholar 

  64. Rius, M., Nies, A. T., Hummel-Eisenbeiss, J., Jedlitschky, G., & Keppler, D. (2003). Cotransport of reduced glutathione with bile salts by MRP4 (ABCC4) localized to the basolateral hepatocyte membrane. Hepatology, 38, 374–384.

    Article  PubMed  CAS  Google Scholar 

  65. Reid, G., Wielinga, P., Zelcer, N., van der Heijden, I., Kuil, A., de Haas, M., et al. (2003). The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proceedings of the National Academy of Sciences of the United States of America, 100, 9244–9249.

    Article  PubMed  CAS  Google Scholar 

  66. Rius, M., Thon, W. F., Keppler, D., & Nies, A. T. (2005). Prostanoid transport by multidrug resistance protein 4 (MRP4/ABCC4) localized in tissues of the human urogenital tract. Journal of Urology, 174, 2409–2414.

    Article  PubMed  CAS  Google Scholar 

  67. Zelcer, N., Reid, G., Wielinga, P., Kuil, A., Van Der Heijden, I., Schuetz, J. D., et al. (2003). Steroid and bile acid conjugates are substrates of human multidrug-resistance protein (MRP) 4 (ATP-binding cassette C4). Biochemical Journal, 371, 361–367.

    Article  PubMed  CAS  Google Scholar 

  68. Van Aubel, R. A., Smeets, P. H., van den Heuvel, J. J., & Russel, F. G. (2005). Human organic anion transporter MRP4 (ABCC4) is an efflux pump for the purine end metabolite urate with multiple allosteric substrate binding sites. Am J Physiol Renal Physiol, 288, F327–F333.

    Article  PubMed  CAS  Google Scholar 

  69. Lai, L., & Tan, T. M. (2002). Role of glutathione in the multidrug resistance protein 4 (MRP4/ABCC4)- mediated efflux of cAMP and resistance to purine analogues. Biochemical Journal, 361, 497–503.

    Article  PubMed  CAS  Google Scholar 

  70. Borst, P., Zelcer, N., van de Wetering, K., & Poolman, B. (2006). On the putative co-transport of drugs by multidrug resistance proteins. FEBS Letters, 580, 1085–1093.

    Article  PubMed  CAS  Google Scholar 

  71. Lee, K., Klein-Szanto, A. J., & Kruh, G. D. (2000). Analysis of the MRP4 drug resistance profile in transfected NIH3T3 cells. Journal of the National Cancer Institute, 92, 1934–1940.

    Article  PubMed  CAS  Google Scholar 

  72. Schuetz, J. D., Connelly, M. C., Sun, D., Paibir, S. G., Flynn, P. M., Srinivas, R. V., et al. (1999). MRP4: A previously unidentified factor in resistance to nucleoside- based antiviral drugs. Natural Medicines, 5, 1048–1051.

    Article  CAS  Google Scholar 

  73. Adachi, M., Sampath, J., Lan, L. B., Sun, D., Hargrove, P., Flatley, R., et al. (2002). Expression of MRP4 confers resistance to ganciclovir and compromises bystander cell killing. Journal of Biological Chemistry, 277, 38998–39004.

    Article  PubMed  CAS  Google Scholar 

  74. Wielinga, P. R., Reid, G., Challa, E. E., van der Heijden, I., van Deemter, L., de Haas, M., et al. (2002). Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Molecular Pharmacology, 62, 1321–1331.

    Article  PubMed  CAS  Google Scholar 

  75. Leggas, M., Adachi, M., Scheffer, G. L., Sun, D., Wielinga, P., Du, G., et al. (2004). Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Molecular and Cellular Biology, 24, 7612–7621.

    Article  PubMed  CAS  Google Scholar 

  76. Norris, M. D., Smith, J., Tanabe, K., Tobin, P., Flemming, C., Scheffer, G. L., et al. (2005). Expression of multidrug transporter MRP4/ABCC4 is a marker of poor prognosis in neuroblastoma and confers resistance to irinotecan in vitro. Mol Cancer Ther, 4, 547–553.

    Article  PubMed  CAS  Google Scholar 

  77. Tian, Q., Zhang, J., Tan, T. M., Chan, E., Duan, W., Chan, S. Y., et al. (2005). Human multidrug resistance associated protein 4 confers resistance to camptothecins. Pharmaceutical Research, 22, 1837–1853.

    Article  PubMed  CAS  Google Scholar 

  78. Kool, M., de Haas, M., Scheffer, G. L., Scheper, R. J., van Eijk, M. J., Juijn, J. A., et al. (1997). Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Research, 57, 3537–3547.

    PubMed  CAS  Google Scholar 

  79. Denk, G. U., Soroka, C. J., Takeyama, Y., Chen, W. S., Schuetz, J. D., & Boyer, J. L. (2004). Multidrug resistance-associated protein 4 is up-regulated in liver but down-regulated in kidney in obstructive cholestasis in the rat. Journal of Hepatology 40, 585–591.

    Article  PubMed  CAS  Google Scholar 

  80. Szakacs, G., Annereau, J.-P., Lababidi, S., Shankavaram, U., Arciello, A., Bussey, K. J., et al. (2004). Predicting drug sensitivity and resistance: Profiling ABC transporter genes in cancer cells. Cancer Cell.

  81. Steinbach, D., Lengemann, J., Voigt, A., Hermann, J., Zintl, F., & Sauerbrey, A. (2003). Response to chemotherapy and expression of the genes encoding the multidrug resistance-associated proteins MRP2, MRP3, MRP4, MRP5, and SMRP in childhood acute myeloid leukemia. Clinical Cancer Research, 9, 1083–1086.

    PubMed  CAS  Google Scholar 

  82. Schuetz, E. G., Strom, S., Yasuda, K., Lecureur, V., Assem, M., Brimer, C., et al. (2001). Disrupted bile acid homeostasis reveals an unexpected interaction among nuclear hormone receptors, transporters, and cytochrome P450. Journal of Biological Chemistry, 276, 39411–39418.

    Article  PubMed  CAS  Google Scholar 

  83. Belinsky, M. G., Guo, P., Lee, K., Zhou, F., Kotova, E., Grinberg, A., et al. (2007). Multidrug resistance protein 4 (Mrp4) protects bone marrow, thymus, spleen and intestine from nucleotide analog-induced damage. Cancer Research, 67, 262–268.

    Google Scholar 

  84. Imaoka, T., Kusuhara, H., Adachi, M., Schuetz, J. D., & Takeuchi, K., Sugiyama, Y. (2006). Functional involvement of multidrug resistance associated protein 4 (MRP4/ABCC4) in the renal elimination of the anti-viral drugs, adefovir and tenofovir. Molecular Pharmacology.

  85. Maher, J. M., Slitt, A. L., Cherrington, N. J., Cheng, X., Klaassen, C. D. (2005). Tissue distribution and hepatic and renal ontogeny of the multidrug resistance-associated protein (Mrp) family in mice. Drug Metabolism and Disposition, 33, 947–955.

    Article  PubMed  CAS  Google Scholar 

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Kruh, G.D., Belinsky, M.G., Gallo, J.M. et al. Physiological and pharmacological functions of Mrp2, Mrp3 and Mrp4 as determined from recent studies on gene-disrupted mice. Cancer Metastasis Rev 26, 5–14 (2007). https://doi.org/10.1007/s10555-007-9039-1

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