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. 1996 Apr;148(4):1237–1247.

Tissue distribution of the multidrug resistance protein.

M J Flens 1, G J Zaman 1, P van der Valk 1, M A Izquierdo 1, A B Schroeijers 1, G L Scheffer 1, P van der Groep 1, M de Haas 1, C J Meijer 1, R J Scheper 1
PMCID: PMC1861521  PMID: 8644864

Abstract

The human multidrug resistance protein (MRP) is a 190 kd membrane glycoprotein that can cause resistance of human tumor cells to various anticancer drugs, by extruding these drugs out of the cell. Three different monoclonal antibodies, directed against different domains of MRP, allowed us to determine the localization of MRP in a panel of normal human tissues and malignant tumors. Whereas in malignant tumors strong plasma membrane MRP staining was frequently observed, in normal human tissues MRP staining was predominantly cytoplasmatic. Here, MRP was detected in several types of epithelia, muscle cells, and macrophages. From the presence of MRP in many epithelia we infer that MRP, like MDR1 P-glycoprotein, may have an excretory function in protecting the organism against xenobiotics. Recent studies indicate a role for MRP as a carrier for transport of glutathione-conjugated endo- and xenobiotics. The presence of MRP in bronchiolar epithelium, heart muscle, and macrophages would agree with the glutathione S-conjugate carrier activity previously detected in these cells. Furthermore, in 46 of 119 untreated tumors from various histogenetic origins MRP staining was seen. In these tumors MRP may contribute to the intrinsic resistance against treatment with chemotherapeutic drugs.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Awasthi S., Singhal S. S., Srivastava S. K., Zimniak P., Bajpai K. K., Saxena M., Sharma R., Ziller S. A., 3rd, Frenkel E. P., Singh S. V. Adenosine triphosphate-dependent transport of doxorubicin, daunomycin, and vinblastine in human tissues by a mechanism distinct from the P-glycoprotein. J Clin Invest. 1994 Mar;93(3):958–965. doi: 10.1172/JCI117102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barrand M. A., Heppell-Parton A. C., Wright K. A., Rabbitts P. H., Twentyman P. R. A 190-kilodalton protein overexpressed in non-P-glycoprotein-containing multidrug-resistant cells and its relationship to the MRP gene. J Natl Cancer Inst. 1994 Jan 19;86(2):110–117. doi: 10.1093/jnci/86.2.110. [DOI] [PubMed] [Google Scholar]
  3. Biedler J. L., Riehm H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro: cross-resistance, radioautographic, and cytogenetic studies. Cancer Res. 1970 Apr;30(4):1174–1184. [PubMed] [Google Scholar]
  4. Burger H., Nooter K., Zaman G. J., Sonneveld P., van Wingerden K. E., Oostrum R. G., Stoter G. Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias. Leukemia. 1994 Jun;8(6):990–997. [PubMed] [Google Scholar]
  5. Center M. S. Non-P-glycoprotein multidrug resistance in cell lines which are defective in the cellular accumulation of drug. Cytotechnology. 1993;12(1-3):109–125. doi: 10.1007/BF00744660. [DOI] [PubMed] [Google Scholar]
  6. Chan H. S., Haddad G., Thorner P. S., DeBoer G., Lin Y. P., Ondrusek N., Yeger H., Ling V. P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma. N Engl J Med. 1991 Dec 5;325(23):1608–1614. doi: 10.1056/NEJM199112053252304. [DOI] [PubMed] [Google Scholar]
  7. Chugani D. C., Rome L. H., Kedersha N. L. Evidence that vault ribonucleoprotein particles localize to the nuclear pore complex. J Cell Sci. 1993 Sep;106(Pt 1):23–29. doi: 10.1242/jcs.106.1.23. [DOI] [PubMed] [Google Scholar]
  8. 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., Deeley R. G. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science. 1992 Dec 4;258(5088):1650–1654. doi: 10.1126/science.1360704. [DOI] [PubMed] [Google Scholar]
  9. Cole S. P., Sparks K. E., Fraser K., Loe D. W., Grant C. E., Wilson G. M., Deeley R. G. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994 Nov 15;54(22):5902–5910. [PubMed] [Google Scholar]
  10. Cole S. P. The 1991 Merck Frosst Award. Multidrug resistance in small cell lung cancer. Can J Physiol Pharmacol. 1992 Mar;70(3):313–329. doi: 10.1139/y92-040. [DOI] [PubMed] [Google Scholar]
  11. Cordon-Cardo C., O'Brien J. P., Casals D., Rittman-Grauer L., Biedler J. L., Melamed M. R., Bertino J. R. Multidrug-resistance gene (P-glycoprotein) is expressed by endothelial cells at blood-brain barrier sites. Proc Natl Acad Sci U S A. 1989 Jan;86(2):695–698. doi: 10.1073/pnas.86.2.695. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Endicott J. A., Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171. doi: 10.1146/annurev.bi.58.070189.001033. [DOI] [PubMed] [Google Scholar]
  13. Flens M. J., Izquierdo M. A., Scheffer G. L., Fritz J. M., Meijer C. J., Scheper R. J., Zaman G. J. Immunochemical detection of the multidrug resistance-associated protein MRP in human multidrug-resistant tumor cells by monoclonal antibodies. Cancer Res. 1994 Sep 1;54(17):4557–4563. [PubMed] [Google Scholar]
  14. Goldstein L. J., Pastan I., Gottesman M. M. Multidrug resistance in human cancer. Crit Rev Oncol Hematol. 1992;12(3):243–253. doi: 10.1016/1040-8428(92)90057-w. [DOI] [PubMed] [Google Scholar]
  15. Gottesman M. M. How cancer cells evade chemotherapy: sixteenth Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res. 1993 Feb 15;53(4):747–754. [PubMed] [Google Scholar]
  16. Grogan T. M., Spier C. M., Salmon S. E., Matzner M., Rybski J., Weinstein R. S., Scheper R. J., Dalton W. S. P-glycoprotein expression in human plasma cell myeloma: correlation with prior chemotherapy. Blood. 1993 Jan 15;81(2):490–495. [PubMed] [Google Scholar]
  17. Hart S. M., Ganeshaguru K., Hoffbrand A. V., Prentice H. G., Mehta A. B. Expression of the multidrug resistance-associated protein (MRP) in acute leukaemia. Leukemia. 1994 Dec;8(12):2163–2168. [PubMed] [Google Scholar]
  18. Higgins C. F. ABC transporters: from microorganisms to man. Annu Rev Cell Biol. 1992;8:67–113. doi: 10.1146/annurev.cb.08.110192.000435. [DOI] [PubMed] [Google Scholar]
  19. Hipfner D. R., Gauldie S. D., Deeley R. G., Cole S. P. Detection of the M(r) 190,000 multidrug resistance protein, MRP, with monoclonal antibodies. Cancer Res. 1994 Nov 15;54(22):5788–5792. [PubMed] [Google Scholar]
  20. Hitchins R. N., Harman D. H., Davey R. A., Bell D. R. Identification of a multidrug resistance associated antigen (P-glycoprotein) in normal human tissues. Eur J Cancer Clin Oncol. 1988 Mar;24(3):449–454. doi: 10.1016/s0277-5379(98)90015-3. [DOI] [PubMed] [Google Scholar]
  21. Horio Y., Takahashi T., Kuroishi T., Hibi K., Suyama M., Niimi T., Shimokata K., Yamakawa K., Nakamura Y., Ueda R. Prognostic significance of p53 mutations and 3p deletions in primary resected non-small cell lung cancer. Cancer Res. 1993 Jan 1;53(1):1–4. [PubMed] [Google Scholar]
  22. Ishikawa T. ATP/Mg2+-dependent cardiac transport system for glutathione S-conjugates. A study using rat heart sarcolemma vesicles. J Biol Chem. 1989 Oct 15;264(29):17343–17348. [PubMed] [Google Scholar]
  23. Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 1992 Nov;17(11):463–468. doi: 10.1016/0968-0004(92)90489-v. [DOI] [PubMed] [Google Scholar]
  24. Jedlitschky G., Leier I., Buchholz U., Center M., Keppler D. ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Res. 1994 Sep 15;54(18):4833–4836. [PubMed] [Google Scholar]
  25. Kondo T., Dale G. L., Beutler E. Studies on glutathione transport utilizing inside-out vesicles prepared from human erythrocytes. Biochim Biophys Acta. 1981 Jul 6;645(1):132–136. doi: 10.1016/0005-2736(81)90520-4. [DOI] [PubMed] [Google Scholar]
  26. Krishnamachary N., Center M. S. The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. Cancer Res. 1993 Aug 15;53(16):3658–3661. [PubMed] [Google Scholar]
  27. Kruh G. D., Gaughan K. T., Godwin A., Chan A. Expression pattern of MRP in human tissues and adult solid tumor cell lines. J Natl Cancer Inst. 1995 Aug 16;87(16):1256–1258. doi: 10.1093/jnci/87.16.1256. [DOI] [PubMed] [Google Scholar]
  28. Leier I., Jedlitschky G., Buchholz U., Cole S. P., Deeley R. G., Keppler D. The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J Biol Chem. 1994 Nov 11;269(45):27807–27810. [PubMed] [Google Scholar]
  29. Leier I., Jedlitschky G., Buchholz U., Keppler D. Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells. Eur J Biochem. 1994 Mar 1;220(2):599–606. doi: 10.1111/j.1432-1033.1994.tb18661.x. [DOI] [PubMed] [Google Scholar]
  30. Müller M., Meijer C., Zaman G. J., Borst P., Scheper R. J., Mulder N. H., de Vries E. G., Jansen P. L. Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):13033–13037. doi: 10.1073/pnas.91.26.13033. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nooter K., Westerman A. M., Flens M. J., Zaman G. J., Scheper R. J., van Wingerden K. E., Burger H., Oostrum R., Boersma T., Sonneveld P. Expression of the multidrug resistance-associated protein (MRP) gene in human cancers. Clin Cancer Res. 1995 Nov;1(11):1301–1310. [PubMed] [Google Scholar]
  32. Rome L., Kedersha N., Chugani D. Unlocking vaults: organelles in search of a function. Trends Cell Biol. 1991 Aug;1(2-3):47–50. doi: 10.1016/0962-8924(91)90088-q. [DOI] [PubMed] [Google Scholar]
  33. Scheffer G. L., Wijngaard P. L., Flens M. J., Izquierdo M. A., Slovak M. L., Pinedo H. M., Meijer C. J., Clevers H. C., Scheper R. J. The drug resistance-related protein LRP is the human major vault protein. Nat Med. 1995 Jun;1(6):578–582. doi: 10.1038/nm0695-578. [DOI] [PubMed] [Google Scholar]
  34. Schinkel A. H., Smit J. J., van Tellingen O., Beijnen J. H., Wagenaar E., van Deemter L., Mol C. A., van der Valk M. A., Robanus-Maandag E. C., te Riele H. P. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994 May 20;77(4):491–502. doi: 10.1016/0092-8674(94)90212-7. [DOI] [PubMed] [Google Scholar]
  35. Schneider E., Cowan K. H., Bader H., Toomey S., Schwartz G. N., Karp J. E., Burke P. J., Kaufmann S. H. Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia. Blood. 1995 Jan 1;85(1):186–193. [PubMed] [Google Scholar]
  36. Schneider E., Horton J. K., Yang C. H., Nakagawa M., Cowan K. H. Multidrug resistance-associated protein gene overexpression and reduced drug sensitivity of topoisomerase II in a human breast carcinoma MCF7 cell line selected for etoposide resistance. Cancer Res. 1994 Jan 1;54(1):152–158. [PubMed] [Google Scholar]
  37. Schuurhuis G. J., Broxterman H. J., Ossenkoppele G. J., Baak J. P., Eekman C. A., Kuiper C. M., Feller N., van Heijningen T. H., Klumper E., Pieters R. Functional multidrug resistance phenotype associated with combined overexpression of Pgp/MDR1 and MRP together with 1-beta-D-arabinofuranosylcytosine sensitivity may predict clinical response in acute myeloid leukemia. Clin Cancer Res. 1995 Jan;1(1):81–93. [PubMed] [Google Scholar]
  38. Slovak M. L., Ho J. P., Bhardwaj G., Kurz E. U., Deeley R. G., Cole S. P. Localization of a novel multidrug resistance-associated gene in the HT1080/DR4 and H69AR human tumor cell lines. Cancer Res. 1993 Jul 15;53(14):3221–3225. [PubMed] [Google Scholar]
  39. Thiebaut F., Tsuruo T., Hamada H., Gottesman M. M., Pastan I., Willingham M. C. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7735–7738. doi: 10.1073/pnas.84.21.7735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Thiebaut F., Tsuruo T., Hamada H., Gottesman M. M., Pastan I., Willingham M. C. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170: evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. J Histochem Cytochem. 1989 Feb;37(2):159–164. doi: 10.1177/37.2.2463300. [DOI] [PubMed] [Google Scholar]
  41. Thomas G. A., Barrand M. A., Stewart S., Rabbitts P. H., Williams E. D., Twentyman P. R. Expression of the multidrug resistance-associated protein (MRP) gene in human lung tumours and normal tissue as determined by in situ hybridisation. Eur J Cancer. 1994;30A(11):1705–1709. doi: 10.1016/0959-8049(94)00290-l. [DOI] [PubMed] [Google Scholar]
  42. Ueda K., Okamura N., Hirai M., Tanigawara Y., Saeki T., Kioka N., Komano T., Hori R. Human P-glycoprotein transports cortisol, aldosterone, and dexamethasone, but not progesterone. J Biol Chem. 1992 Dec 5;267(34):24248–24252. [PubMed] [Google Scholar]
  43. Zaman G. J., Flens M. J., van Leusden M. R., de Haas M., Mülder H. S., Lankelma J., Pinedo H. M., Scheper R. J., Baas F., Broxterman H. J. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8822–8826. doi: 10.1073/pnas.91.19.8822. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Zaman G. J., Versantvoort C. H., Smit J. J., Eijdems E. W., de Haas M., Smith A. J., Broxterman H. J., Mulder N. H., de Vries E. G., Baas F. Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Res. 1993 Apr 15;53(8):1747–1750. [PubMed] [Google Scholar]
  45. Zimniak P., Awasthi Y. C. ATP-dependent transport systems for organic anions. Hepatology. 1993 Feb;17(2):330–339. [PubMed] [Google Scholar]
  46. van Kalken C. K., Broxterman H. J., Pinedo H. M., Feller N., Dekker H., Lankelma J., Giaccone G. Cortisol is transported by the multidrug resistance gene product P-glycoprotein. Br J Cancer. 1993 Feb;67(2):284–289. doi: 10.1038/bjc.1993.54. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. van der Valk P., van Kalken C. K., Ketelaars H., Broxterman H. J., Scheffer G., Kuiper C. M., Tsuruo T., Lankelma J., Meijer C. J., Pinedo H. M. Distribution of multi-drug resistance-associated P-glycoprotein in normal and neoplastic human tissues. Analysis with 3 monoclonal antibodies recognizing different epitopes of the P-glycoprotein molecule. Ann Oncol. 1990;1(1):56–64. [PubMed] [Google Scholar]

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