Skip to main content
SpringerLink
Log in

MRP Subfamily Transporters and Resistance to Anticancer Agents

  • Published:
Journal of Bioenergetics and Biomembranes Aims and scope Submit manuscript

Abstract

The MRP subfamily of ABC transporters from mammals consists of at least seven members, six of which have been implicated in the transport of amphipathic anions. MRP1, MRP2, and MRP3 bear a close structural resemblance, confer resistance to a variety of natural products as well as methotrexate, and have the facility for transporting glutathione and glucuronate conjugates. MRP1 is a ubiquitously expressed efflux pump for the products of phase II of xenobiotic detoxification, while MRP2, whose hereditary deficiency results in Dubin–Johnson syndrome, functions to extrude organic anions into the bile. MRP3 is distinguished by its capacity to transport the monoanionic bile constituent glycocholate, and may function as a basolateral back-up system for the detoxification of hepatocytes when the usual canalicular route is impaired by cholestatic conditions. MRP4 and MRP5 resemble each other more closely than they resemble MRPs 1–3 and confer resistance to purine and nucleotide analogs which are either inherently anionic, as in the case of the anti-AIDS drug PMEA, or are phosphorylated and converted to anionic amphiphiles in the cell, as in the case of 6-MP. Given their capacity for transporting cyclic nucleotides, MRP4 and MRP5 have also been implicated in a broad range of cellular signaling processes. The drug resistance activity and physiological substrates of MRP6 are unknown. However, its hereditary deficiency results in pseudoxanthoma elasticum, a multisystem disorder affecting skin, eyes, and blood vessels. It is hoped that elucidation of the resistance profiles and physiological functions of the different members of the MRP subfamily will provide new insights into the molecular basis of clinical drug resistance and spawn new strategies for combating this phenomenon.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

REFERENCES

  • Allikmets, R., Gerrard, B., Hutchinson, A., and Dean, M. (1996). Hum. Mol. Genet. 5, 1649–1655.

    Google Scholar 

  • Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V., and Dean, M. (1998). Cancer Res. 58, 5337–5339.

    Google Scholar 

  • Bakos, E., Evers, R., Szakacs, G., Tusnady, G. E., Welker, E., Szabo, K., de Haas, M., van Deemter, L., Borst, P., Varadi, A., and Sarkadi, B. (1998). J. Biol. Chem. 273, 32167–32175.

    Google Scholar 

  • Bartosz, G., Konig, J., Keppler, D., and Hagmann, W. (1998). Biol. Chem. 379, 1121–1126.

    Google Scholar 

  • Belinsky, M. G., Bain, L. J., Balsara, B. B., Testa, J. R., and Kruh, G. D. (1998). J. Natl. Cancer Inst. 90, 1735–1741.

    Google Scholar 

  • Belinsky, M. G., and Kruh, G. D. (1999). Br. J. Cancer. 80, 1342–1349.

    Google Scholar 

  • Bergen, A. A., Plomp, A. S., Schuurman, E. J., Terry, S., Breuning, M., Dauwerse, H., Swart, J., Kool, M., van Soest, S., Baas, F., ten Brink, J. B., and de Jong, P. T. (2000). Nat. Genet. 25, 228–231.

    Google Scholar 

  • Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A., and Kruh, G. D. (1995). Cancer Res. 55, 5342–5347.

    Google Scholar 

  • Buchler, M., Konig, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., and Keppler, D. (1996). J. Biol. Chem. 271, 15091–15098.

    Google Scholar 

  • Chen, Z. S., Lee, K., and Kruh, G. D. (2001). J. Biol. Chem. 276, 33747–33754.

    Google Scholar 

  • Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., Stewart, A. J., Kurz, E. U., Duncan, A. M., and Deeley, R. G. (1992). Science 258, 1650–1654.

    Google Scholar 

  • Cole, S. P., Sparks, K. E., Fraser, K., Loe, D. W., Grant, C. E., Wilson, G. M., and Deeley, R. G. (1994). Cancer Res. 54, 5902–5910.

    Google Scholar 

  • Cui, Y., Konig, J., Buchholz, J. K., Spring, H., Leier, I., and Keppler, D. (1999). Mol. Pharmacol. 55, 929–937.

    Google Scholar 

  • Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., and Ross, D. D. (1998). Proc. Natl. Acad. Sci. U.S.A. 95, 15665–15670.

    Google Scholar 

  • Elferink, R. P., Ottenhoff, R., Liefting, W., de Haan, J., and Jansen, P. L. (1989). J. Clin. Invest. 84, 476–483.

    Google Scholar 

  • Evers, R., de Haas, M., Sparidans, R., Beijnen, J., Wielinga, P. R., Lankelma, J., and Borst, P. (2000). Br. J. Cancer. 83, 375–383.

    Google Scholar 

  • Evers, R., Kool, M., van Deemter, L., Janssen, H., Calafat, J., Oomen, L. C., Paulusma, C. C., Oude Elferink, R. P., Baas, F., Schinkel, A. H., and Borst, P. (1998). J. Clin. Invest. 101, 1310–1319.

    Google Scholar 

  • Evers, R., Zaman, G. J., van Deemter, L., Jansen, H., Calafat, J., Oomen, L. C., Oude Elferink, R. P., Borst, P., and Schinkel, A. H. (1996). J. Clin. Invest. 97, 1211–1218.

    Google Scholar 

  • Gottesman, M. M., and Pastan, I. (1993). Annu. Rev. Biochem. 62, 385–427.

    Google Scholar 

  • Grant, C. E., Valdimarsson, G., Hipfner, D. R., Almquist, K. C., Cole, S. P., and Deeley, R. G. (1994). Cancer Res. 54, 357–361.

    Google Scholar 

  • Hirohashi, T., Suzuki, H., Chu, X. Y., Tamai, I., Tsuji, A., and Sugiyama, Y. (2000). J. Pharmacol. Exp. Ther. 292, 265–270.

    Google Scholar 

  • Hirohashi, T., Suzuki, H., Ito, K., Ogawa, K., Kume, K., Shimizu, T., and Sugiyama, Y. (1998). Mol. Pharmacol. 53, 1068–1075.

    Google Scholar 

  • Hooijberg, J. H., Broxterman, H. J., Kool, M., Assaraf, Y. G., Peters, G. J., Noordhuis, P., Scheper, R. J., Borst, P., Pinedo, H. M., and Jansen, G. (1999). Cancer Res. 59, 2532–2535.

    Google Scholar 

  • Ishikawa, T., and Ali-Osman, F. (1993). J. Biol. Chem. 268, 20116–20125.

    Google Scholar 

  • Ishikawa, T., Bao, J. J., Yamane, Y., Akimaru, K., Frindrich, K., Wright, C. D., and Kuo, M. T. (1996). J. Biol. Chem. 271, 14981–14988.

    Google Scholar 

  • Ishikawa, T., Muller, M., Klunemann, C., Schaub, T., and Keppler, D. (1990). J. Biol. Chem. 265, 19279–19286.

    Google Scholar 

  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y. (1998). J. Biol. Chem. 273, 1684–1688.

    Google Scholar 

  • Ito, K., Suzuki, H., Hirohashi, T., Kume, K., Shimizu, T., and Sugiyama, Y. (1997). Am. J. Physiol. 272, G16–G22.

    Google Scholar 

  • Jedlitschky, G., Burchell, B., and Keppler, D. (2000). J. Biol. Chem. 275, 30069–30074.

    Google Scholar 

  • Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., and Keppler, D. (1996). Cancer Res. 56, 988–994.

    Google Scholar 

  • Jedlitschky, G., Leier, I., Buchholz, U., Center, M., and Keppler, D. (1994). Cancer Res. 54, 4833–4836.

    Google Scholar 

  • Kartenbeck, J., Leuschner, U., Mayer, R., and Keppler, D. (1996). Hepatology 23, 1061–1066.

    Google Scholar 

  • Kawabe, T., Chen, Z. S., Wada, M., Uchiumi, T., Ono, M., Akiyama, S., and Kuwano, M. (1999). FEBS Lett. 456, 327–331.

    Google Scholar 

  • Kitamura, T., Jansen, P., Hardenbrook, C., Kamimoto, Y., Gatmaitan, Z., and Arias, I. M. (1990). Proc. Natl. Acad. Sci. U.S.A. 87, 3557–3561.

    Google Scholar 

  • Koike, K., Kawabe, T., Tanaka, T., Toh, S., Uchiumi, T., Wada, M., Akiyama, S., Ono, M., and Kuwano, M. (1997). Cancer Res. 57, 5475–5479.

    Google Scholar 

  • Konig, J., Rost, D., Cui, Y., and Keppler, D. (1999). Hepatology 29, 1156–1163.

    Google Scholar 

  • Kool, M., de Haas, M., Scheffer, G. L., Scheper, R. J., van Eijk, M. J., Juijn, J. A., Baas, F., and Borst, P. (1997). Cancer Res. 57, 3537–3547.

    Google Scholar 

  • Kool, M., van der Linden, M., de Haas, M., Baas, F., and Borst, P. (1999a). Cancer Res. 59, 175–182.

    Google Scholar 

  • Kool, M., van der Linden, M., de Haas, M., Scheffer, G. L., de Vree, J. M., Smith, A. J., Jansen, G., Peters, G. J., Ponne, N., Scheper, R. J., Elferink, R. P., Baas, F., and Borst, P. (1999b). Proc. Natl. Acad. Sci. U.S.A. 96, 6914–6919.

    Google Scholar 

  • Krishnamachary, N., and Center, M. S. (1993). Cancer Res. 53, 3658–3661.

    Google Scholar 

  • Kruh, G. D., Chan, A., Myers, K., Gaughan, K., Miki, T., and Aaronson, S. A. (1994). Cancer Res. 54, 1649–1652.

    Google Scholar 

  • Kruh, G. D., Gaughan, K. T., Godwin, A., and Chan, A. (1995). J. Natl. Cancer. Inst. 87, 1256–1258.

    Google Scholar 

  • Kuo, M. T., Bao, J. J., Curley, S. A., Ikeguchi, M., Johnston, D. A., and Ishikawa, T. (1996). Cancer Res. 56, 3642–3644.

    Google Scholar 

  • Lacave, R., Coulet, F., Ricci, S., Touboul, E., Flahault, A., Rateau, J. G., Cesari, D., Lefranc, J. P., and Bernaudin, J. F. (1998). Br. J. Cancer. 77, 694–702.

    Google Scholar 

  • Laing, N. M., Belinsky, M. G., Kruh, G. D., Bell, D. W., Boyd, J. T., Barone, L., Testa, J. R., and Tew, K. D. (1998). Cancer Res. 58, 1332–1337.

    Google Scholar 

  • Le Saux, O., Urban, Z., Tschuch, C., Csiszar, K., Bacchelli, B., Quaglino, D., Pasquali-Ronchetti, I., Pope, F. M., Richards, A., Terry, S., Bercovitch, L., de Paepe, A., and Boyd, C. D. (2000). Nat. Genet. 25, 223–227.

    Google Scholar 

  • Lee, K., Belinsky, M. G., Bell, D. W., Testa, J. R., and Kruh, G. D. (1998). Cancer Res. 58, 2741–2747.

    Google Scholar 

  • Lee, K., Klein-Szanto, A., and Kruh, G. D. (2000). J. Natl. Cancer. Inst. 92, 1934–1940.

    Google Scholar 

  • Leier, I., Jedlitschky, G., Buchholz, U., Cole, S. P., Deeley, R. G., and Keppler, D. (1994). J. Biol. Chem. 269, 27807–27810.

    Google Scholar 

  • Ling, V. (1997). Cancer Chemother. Pharmacol. 40, S3–S8.

    Google Scholar 

  • Loe, D. W., Almquist, K. C., Cole, S. P., and Deeley, R. G. (1996a). J. Biol. Chem. 271, 9683–9689.

    Google Scholar 

  • Loe, D. W., Almquist, K. C., Deeley, R. G., and Cole, S. P. (1996b). J. Biol. Chem. 271, 9675–9682.

    Google Scholar 

  • Longhurst, T. J., O'Neill, G. M., Harvie, R. M., and Davey, R. A. (1996). Br. J. Cancer 74, 1331–1335.

    Google Scholar 

  • Lorico, A., Rappa, G., Finch, R. A., Yang, D., Flavell, R. A., and Sartorelli, A. C. (1997). Cancer Res. 57, 5238–5242.

    Google Scholar 

  • Lorico, A., Rappa, G., Flavell, R. A., and Sartorelli, A. C. (1996). Cancer Res. 56, 5351–5355.

    Google Scholar 

  • Lutzky, J., Astor, M. B., Taub, R. N., Baker, M. A., Bhalla, K., Gervasoni, J. E., Jr., Rosado, M., Stewart, V., Krishna, S., and Hindenburg, A. A. (1989). Cancer Res. 49, 4120–4125.

    Google Scholar 

  • Madon, J., Eckhardt, U., Gerloff, T., Stieger, B., and Meier, P. J. (1997). FEBS Lett. 406, 75–78.

    Google Scholar 

  • Madon, J., Hagenbuch, B., Landmann, L., Meier, P. J., and Stieger, B. (2000). Mol. Pharmacol. 57, 634–641.

    Google Scholar 

  • Marquardt, D., McCrone, S., and Center, M. S. (1990). Cancer Res. 50, 1426–1430.

    Google Scholar 

  • Marsh, W., and Center, M. S. (1987). Cancer Res. 47, 5080–5161.

    Google Scholar 

  • Marsh, W., Sicheri, D., and Center, M. S. (1986). Cancer Res. 46, 4053–4057.

    Google Scholar 

  • Masuda, M., I'izuka, Y., Yamazaki, M., Nishigaki, R., Kato, Y., Ni'inuma, K., Suzuki, H., and Sugiyama, Y. (1997). Cancer Res. 57, 3506–3510.

    Google Scholar 

  • Mayer, R., Kartenbeck, J., Buchler, M., Jedlitschky, G., Leier, I., and Keppler, D. (1995). J. Cell. Biol. 131, 137–150.

    Google Scholar 

  • McAleer, M. A., Breen, M. A., White, N. L., and Matthews, N. (1999). J. Biol. Chem. 274, 23541–23548.

    Google Scholar 

  • McGrath, T., and Center, M. S. (1987). Biochem. Biophys. Res. Commun. 145, 1171–1176.

    Google Scholar 

  • McGrath, T., Latoud, C., Arnold, S. T., Safa, A. R., Felsted, R. L., and Center, M. S. (1989). Biochem. Pharmacol. 38, 3611–3619.

    Google Scholar 

  • Miyake, K., Mickley, L., Litman, T., Zhan, Z., Robey, R., Cristensen, B., Brangi, M., Greenberger, L., Dean, M., Fojo, T., and Bates, S. E. (1999). Cancer Res. 59, 8–13.

    Google Scholar 

  • Morrow, C. S., Smitherman, P. K., Diah, S. K., Schneider, E., and Townsend, A. J. (1998). J. Biol. Chem. 273, 20114–20120.

    Google Scholar 

  • O'Brien, M., Kruh, G. D., and Tew, K. D. (2000). J. Pharmacol. Exp. Ther. 294, 480–487.

    Google Scholar 

  • Ortiz, D. F., Li, S., Iyer, R., Zhang, X., Novikoff, P., and Arias, I. M. (1999). Am. J. Physiol. 276, G1493–G1500.

    Google Scholar 

  • Paulusma, C. C., Bosma, P. J., Zaman, G. J., Bakker, C. T., Otter, M., Scheffer, G. L., Scheper, R. J., Borst, P., and Oude Elferink, R. P. (1996). Science 271, 1126–1128.

    Google Scholar 

  • Paulusma, C. C., Kool, M., Bosma, P. J., Scheffer, G. L., ter Borg, F., Scheper, R. J., Tytgat, G. N., Borst, P., Baas, F., and Oude Elferink, R. P. (1997). Hepatology 25, 1539–1542.

    Google Scholar 

  • Paulusma, C. C., van Geer, M. A., Evers, R., Heijn, M., Ottenhoff, R., Borst, P., and Oude Elferink, R. P. (1999). Biochem. J. 338, 393–401.

    Google Scholar 

  • Ringpfeil, F., Lebwohl, M. G., Christiano, A. M., and Uitto, J. (2000). Proc. Natl. Acad. Sci. U.S.A. 97, 6001–6006.

    Google Scholar 

  • Saxena, M., and Henderson, G. B. (1995). J. Biol. Chem. 270, 5312–5319.

    Google Scholar 

  • Schneider, E., Yamazaki, H., Sinha, B. K., and Cowan, K. H. (1995). Br. J. Cancer. 71, 738–743.

    Google Scholar 

  • Schuetz, J. D., Connelly, M. C., Sun, D., Paibir, S. G., Flynn, P. M., Srinivas, R. V., Kumar, A., and Fridland, A. (1999). Nat. Med. 5, 1048–1051.

    Google Scholar 

  • Suzuki, T., Nishio, K., Sasaki, H., Kurokawa, H., Saito-Ohara, F., Ikeuchi, T., Tanabe, S., Terada, M., and Saijo, N. (1997). Biochem. Biophys. Res. Commun. 238, 790–794.

    Google Scholar 

  • Takikawa, H., Sano, N., Narita, T., Uchida, Y., Yamanaka, M., Horie, T., Mikami, T., and Tagaya, O. (1991). Hepatology 14, 352–360.

    Google Scholar 

  • Taniguchi, K., Wada, M., Kohno, K., Nakamura, T., Kawabe, T., Kawakami, M., Kagotani, K., Okumura, K., Akiyama, S., and Kuwano, M. (1996). Cancer Res. 56, 4124–4129.

    Google Scholar 

  • Tusnady, G. E., Bakos, E., Varadi, A., and Sarkadi, B. (1997). FEBS Lett. 402, 1–3.

    Google Scholar 

  • Uchiumi, T., Hinoshita, E., Haga, S., Nakamura, T., Tanaka, T., Toh, S., Furukawa, M., Kawabe, T., Wada, M., Kagotani, K., Okumura, K., Kohno, K., Akiyama, S., and Kuwano, M. (1998). Biochem. Biophys. Res. Commun. 252, 103–110.

    Google Scholar 

  • van Aubel, R. A., Koenderink, J. B., Peters, J. G., Van Os, C. H., and Russel, F. G. (1999). Mol. Pharmacol. 56, 714–719.

    Google Scholar 

  • van Aubel, R. A., van Kuijck, M. A., Koenderink, J. B., Deen, P. M., van Os, C. H., and Russel, F. G. (1998). Mol. Pharmacol. 53, 1062–1067.

    Google Scholar 

  • Versantvoort, C. H., Broxterman, H. J., Bagrij, T., Scheper, R. J., and Twentyman, P. R. (1995). Br. J. Cancer. 72, 82–89.

    Google Scholar 

  • Wijnholds, J., Evers, R., van Leusden, M. R., Mol, C. A., Zaman, G. J., Mayer, U., Beijnen, J. H., van der Valk, M., Krimpenfort, P., and Borst, P. (1997). Nat. Med. 3, 1275–1279.

    Google Scholar 

  • Wijnholds, J., Mol, C. A., van Deemter, L., de Haas, M., Scheffer, G. L., Baas, F., Beijnen, J. H., Scheper, R. J., Hatse, S., De Clercq, E., Balzarini, J., and Borst, P. (2000). Proc. Natl. Acad. Sci. U.S.A. 97, 7476–7481.

    Google Scholar 

  • Wijnholds, J., Scheffer, G. L., van der Valk, M., van der Valk, P., Beijnen, J. H., Scheper, R. J., and Borst, P. (1998). J. Exp. Med. 188, 797–808.

    Google Scholar 

  • Zaman, G. J., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., Pinedo, H. M., Scheper, R. J., Baas, F., Broxterman, H. J., and Borst, P. (1994). Proc. Natl. Acad. Sci.U.S.A. 91, 8822–8826.

    Google Scholar 

  • Zaman, G. J., Lankelma, J., van Tellingen, O., Beijnen, J., Dekker, H., Paulusma, C., Oude Elferink, R. P., Baas, F., and Borst, P. (1995). Proc. Natl. Acad. Sci. U.S.A. 92, 7690–7694.

    Google Scholar 

  • Zeng, H., Bain, L. J., Belinsky, M. G., and Kruh, G. D. (1999). Cancer Res. 59, 5964–5967.

    Google Scholar 

  • Zeng, H., Liu, G., Rea, P. A., and Kruh, G. D. (2000). Cancer Res. 60, 4779–4784.

    Google Scholar 

  • Zeng, H., Chen, Z. S., Belinsky, M. G., Rea, P. A., and Kruh, G. D. (2001). Cancer Res. 61, 7225–7232.

    Google Scholar 

Download references

Authors
  1. Gary D. Kruh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hao Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philip A. Rea
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guosheng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhe-Sheng Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kun Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Martin G. Belinsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kruh, G.D., Zeng, H., Rea, P.A. et al. MRP Subfamily Transporters and Resistance to Anticancer Agents. J Bioenerg Biomembr 33, 493–501 (2001). https://doi.org/10.1023/A:1012827221844

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1012827221844

Search

Navigation