Abstract
Over a million new cases of cancers are diagnosed each year in the United States and over half of these patients die from these devastating diseases. Thus, cancers cause a major public health problem in the United States and worldwide. Chemotherapy remains the principal mode to treat many metastatic cancers. However, occurrence of cellular multidrug resistance (MDR) prevents efficient killing of cancer cells, leading to chemotherapeutic treatment failure. Numerous mechanisms of MDR exist in cancer cells, such as intrinsic or acquired MDR. Overexpression of ATP-binding cassette (ABC) drug transporters, such as P-glycoprotein (P-gp or ABCB1), breast cancer resistance protein (BCRP or ABCG2) and/or multidrug resistance-associated protein (MRP1 or ABCC1), confers an acquired MDR due to their capabilities of transporting a broad range of chemically diverse anticancer drugs. In addition to their roles in MDR, there is substantial evidence suggesting that these drug transporters have functions in tissue defense. Basically, these drug transporters are expressed in tissues important for absorption, such as in lung and gut, and for metabolism and elimination, such as in liver and kidney. In addition, these drug transporters play an important role in maintaining the barrier function of many tissues including blood-brain barrier, blood-cerebral spinal fluid barrier, blood-testis barrier and the maternal-fetal barrier. Thus, these ATP-dependent drug transporters play an important role in the absorption, disposition and elimination of the structurally diverse array of the endobiotics and xenobiotics. In this review, the molecular mechanism of ATP-dependent solute transport by MRP1 will be addressed.
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Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., et al. (2001). The sequence of the human genome. Science, 291, 1304–1351.
Choudhuri, S., & Klaassen, C. D. (2006). Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. International Journal of Toxicology, 25, 231–259.
Cole, S. P., Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C. E., Almquist, K. C., et al. (1992). Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line [see comments]. Science, 258, 1650–1654.
Mirski, S. E., Gerlach, J. H., & Cole, S. P. (1987). Multidrug resistance in a human small cell lung cancer cell line selected in adriamycin. Cancer Research, 47, 2594–2598.
Cole, S. P., Chanda, E. R., Dicke, F. P., Gerlach, J. H., & Mirski, S. E. (1991). Non-P-glycoprotein-mediated multidrug resistance in a small cell lung cancer cell line: Evidence for decreased susceptibility to drug-induced DNA damage and reduced levels of topoisomerase II. Cancer Research, 51, 3345–3352.
Grant, C. E., Valdimarsson, G., Hipfner, D. R., Almquist, K. C., Cole, S. P., & Deeley, R. G. (1994). Overexpression of multidrug resistance-associated protein (MRP) increases resistance to natural product drugs. Cancer Research, 54, 357–361.
Marquardt, D., McCrone, S., & Center, M. S. (1990). Mechanisms of multidrug resistance in HL60 cells: Detection of resistance-associated proteins with antibodies against synthetic peptides that correspond to the deduced sequence of P-glycoprotein. Cancer Research, 50, 1426–1430.
Krishnamachary, N., & Center, M. S. (1993). The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein. Cancer Research, 53, 3658–3661.
Juliano, R. L., & Ling, V. (1976). A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica et Biophysica Acta, 455, 152–162.
Slovak, M. L., Ho, J. P., Bhardwaj, G., Kurz, E. U., Deeley, R. G., & Cole, S. P. (1993). Localization of a novel multidrug resistance-associated gene in the HT1080/DR4 and H69AR human tumor cell lines. Cancer Research, 53, 3221–3225.
Grant, C. E., Kurz, E. U., Cole, S. P., & Deeley, R. G. (1997). Analysis of the intron-exon organization of the human multidrug-resistance protein gene (MRP) and alternative splicing of its mRNA. Genomics, 45, 368–378.
Hipfner, D. R., Deeley, R. G., & Cole, S. P. (1999). Structural, mechanistic and clinical aspects of MRP1. Biochimica et Biophysica Acta, 1461, 359–376.
Borst, P., Evers, R., Kool, M., & Wijnholds, J. (1999). The multidrug resistance protein family. Biochimica et Biophysica Acta, 1461, 347–357.
Dean, M., Rzhetsky, A., & Allikmets, R. (2001). The human ATP-binding cassette (ABC) transporter superfamily. Genome Research, 11, 1156–1166.
Cole, S. P., & Deeley, R. G. (1998). Multidrug resistance mediated by the ATP-binding cassette transporter protein MRP. Bioessays, 20, 931–940.
Gao, M., Cui, H. R., Loe, D. W., Grant, C. E., Almquist, K. C., Cole, S. P., et al. (2000). Comparison of the functional characteristics of the nucleotide binding domains of multidrug resistance protein 1. Journal of Biological Chemistry, 275, 13098–13108.
Chen, C. J., Chin, J. E., Ueda, K., Clark, D. P., Pastan, I., Gottesman, M. M., et al. (1986). Internal duplication and homology with bacterial transport proteins in the mdr1 (P-glycoprotein) gene from multidrug-resistant human cells. Cell, 47, 381–389.
Zhang, J. T., & Ling, V. (1991). Study of membrane orientation and glycosylated extracellular loops of mouse P-glycoprotein by in vitro translation. Journal of Biological Chemistry, 266, 18224–18232.
Gros, P., Croop, J., & Housman, D. (1986). Mammalian multidrug resistance gene: Complete cDNA sequence indicates strong homology to bacterial transport proteins. Cell, 47, 371–380.
Gerlach, J. H., Endicott, J. A., Juranka, P. F., Henderson, G., Sarangi, F., Deuchars, K. L., et al. (1986). Homology between P-glycoprotein and a bacterial haemolysin transport protein suggests a model for multidrug resistance. Nature, 324, 485–489.
Bakos, E., Hegedus, T., Hollo, Z., Welker, E., Tusnady, G. E., Zaman, G. J., et al. (1996). Membrane topology and glycosylation of the human multidrug resistance-associated protein. Journal of Biological Chemistry, 271, 12322–12326.
Hipfner, D. R., Almquist, K. C., Leslie, E. M., Gerlach, J. H., Grant, C. E., Deeley, R. G., et al. (1997). Membrane topology of the multidrug resistance protein (MRP). A study of glycosylation-site mutants reveals an extracytosolic NH2 terminus. Journal of Biological Chemistry, 272, 23623–23630.
Borst, P., Evers, R., Kool, M., & Wijnholds, J. (2000). A family of drug transporters: The multidrug resistance-associated proteins. Journal of National Cancer Institute, 92, 1295–1302.
Riordan, J. R., Rommens, J. M., Kerem, B., Alon, N., Rozmahel, R., Grzelczak, Z., et al. (1989). Identification of the cystic fibrosis gene: Cloning and characterization of complementary DNA. Science, 245, 1066–1073.
Lee, S. H., & Altenberg, G. A. (2003). Transport of leukotriene C4 by a cysteine-less multidrug resistance protein 1 (MRP1). Biochemical Journal, 370, 357–360.
Bakos, E., Evers, R., Szakacs, G., Tusnady, G. E., Welker, E., Szabo, K., et al. (1998). Functional multidrug resistance protein (MRP1) lacking the N-terminal transmembrane domain. Journal of Biological Chemistry, 273, 32167–32175.
Krishnamachary, N., Ma, L., Zheng, L., Safa, A. R., & Center, M. S. (1994). Analysis of MRP gene expression and function in HL60 cells isolated for resistance to adriamycin. Oncology Research, 6, 119–127.
Almquist, K. C., Loe, D. W., Hipfner, D. R., Mackie, J. E., Cole, S. P., & Deeley, R. G. (1995). Characterization of the M(r) 190,000 multidrug resistance protein (MRP) in drug-selected and transfected human tumor cell. Cancer Research, 55, 102–110.
Zaman, G. J., Flens, M. J., van Leusden, M. R., de Haas, M., Mulder, H. S., Lankelma, J., et al. (1994). The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Proceedings of the National Academy of Sciences of the United States of America, 91, 8822–8826.
Cole, S. P., Sparks, K. E., Fraser, K., Loe, D. W., Grant, C. E., Wilson, G. M., et al. (1994). Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Research, 54, 5902–5910.
Chang, X. B., Hou, Y. X., & Riordan, J. R. (1997). ATPase activity of purified multidrug resistance-associated protein [published erratum appears in J Biol Chem 1998 Mar 27;273(13):7782]. Journal of Biological Chemistry, 272, 30962–30968.
Leslie, E. M., Deeley, R. G., & Cole, S. P. (2001). Toxicological relevance of the multidrug resistance protein 1, MRP1 (ABCC1) and related transporters. Toxicology, 167, 3–23.
Loe, D. W., Almquist, K. C., Deeley, R. G., & Cole, S. P. (1996). Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. Demonstration of glutathione-dependent vincristine transport. Journal of Biological Chemistry, 271, 9675–9682.
Renes, J., de Vries, E. G., Nienhuis, E. F., Jansen, P. L., & Muller, M. (1999). ATP- and glutathione-dependent transport of chemotherapeutic drugs by the multidrug resistance protein MRP1. British Journal of Pharmacology, 126, 681–688.
Loe, D. W., Deeley, R. G., & Cole, S. P. (1998). Characterization of vincristine transport by the M(r) 190,000 multidrug resistance protein (MRP): Evidence for cotransport with reduced glutathione. Cancer Research, 58, 5130–5136.
Salerno, M., & Garnier-Suillerot, A. (2001). Kinetics of glutathione and daunorubicin efflux from multidrug resistance protein overexpressing small-cell lung cancer cells. European Journal of Pharmacology, 421, 1–9.
Leier, I., Jedlitschky, G., Buchholz, U., Center, M., Cole, S. P., Deeley, R. G., et al. (1996). ATP-dependent glutathione disulphide transport mediated by the MRP gene-encoded conjugate export pump. Biochemical Journal, 314, 433–437.
Leslie, E. M., Deeley, R. G., & Cole, S. P. (2003). Bioflavonoid stimulation of glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). Drug Metabolism and Disposition, 31, 11–15.
Manciu, L., Chang, X. B., Buyse, F., Hou, Y. X., Gustot, A., Riordan, J. R., et al. (2003). Intermediate structural states involved in MRP1-mediated drug transport. Role of glutathione. Journal of Biological Chemistry, 278, 3347–3356.
Hou, Y., Cui, L., Riordan, J. R., & Chang, X. B. (2000). Allosteric interactions between the two non-equivalent nucleotide binding domains of multidrug resistance protein MRP1. Journal of Biological Chemistry, 275, 20280–20287.
Loe, D. W., Deeley, R. G., & Cole, S. P. (2000). Verapamil stimulates glutathione transport by the 190-kDa multidrug resistance protein 1 (MRP1). Journal of Pharmacology and Experimental Therapeutics, 293, 530–538.
Leslie, E. M., Mao, Q., Oleschuk, C. J., Deeley, R. G., & Cole, S. P. (2001). Modulation of multidrug resistance protein 1 (MRP1/ABCC1) transport and atpase activities by interaction with dietary flavonoids. Molecular Pharmacology, 59, 1171–1180.
Leier, I., Jedlitschky, G., Buchholz, U., & Keppler, D. (1994). Characterization of the ATP-dependent leukotriene C4 export carrier in mastocytoma cells. European Journal of Biochemistry, 220, 599–606.
Keppler, D., Leier, I., & Jedlitschky, G. (1997). Transport of glutathione conjugates and glucuronides by the multidrug resistance proteins MRP1 and MRP2. Biological Chemistry, 378, 787–791.
Jedlitschky, G., Leier, I., Buchholz, U., Barnouin, K., Kurz, G., & Keppler, D. (1996). Transport of glutathione, glucuronate, and sulfate conjugates by the MRP gene-encoded conjugate export pump. Cancer Research, 56, 988–994.
Jedlitschky, G., Leier, I., Buchholz, U., Hummel-Eisenbeiss, J., Burchell, B., & Keppler, D. (1997). ATP-dependent transport of bilirubin glucuronides by the multidrug resistance protein MRP1 and its hepatocyte canalicular isoform MRP2. Biochemical Journal, 327(Pt 1), 305–310.
Loe, D. W., Almquist, K. C., Cole, S. P., & Deeley, R. G. (1996). ATP-dependent 17 beta-estradiol 17-(beta-D-glucuronide) transport by multidrug resistance protein (MRP). Inhibition by cholestatic steroids. Journal of Biological Chemistry, 271, 9683–9689.
Jedlitschky, G., Leier, I., Buchholz, U., Center, M., & Keppler, D. (1994). ATP-dependent transport of glutathione S-conjugates by the multidrug resistance-associated protein. Cancer Research, 54, 4833–4836.
Leier, I., Jedlitschky, G., Buchholz, U., Cole, S. P., Deeley, R. G., & Keppler, D. (1994). The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. Journal of Biological Chemistry, 269, 27807–27810.
Muller, M., Meijer, C., Zaman, G. J., Borst, P., Scheper, R. J., Mulder, N. H., et al. (1994). Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport. Proceedings of the National Academy of Sciences of the United States of America, 91, 13033–13037.
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.
Leslie, E. M., Bowers, R. J., Deeley, R. G., & Cole, S. P. (2003). Structural requirements for functional interaction of glutathione tripeptide analogs with the human multidrug resistance protein 1 (MRP1). Journal of Pharmacology and Experimental Therapeutics, 304, 643–653.
Qian, Y. M., Song, W. C., Cui, H., Cole, S. P., & Deeley, R. G. (2001). Glutathione stimulates sulfated estrogen transport by multidrug resistance protein 1. Journal of Biological Chemistry, 276, 6404–6411.
Leslie, E. M., Ito, K., Upadhyaya, P., Hecht, S. S., Deeley, R. G., & Cole, S. P. (2001). Transport of the beta -O-glucuronide conjugate of the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) by the multidrug resistance protein 1 (MRP1). Requirement for glutathione or a non-sulfur-containing analog. Journal of Biological Chemistry, 276, 27846–27854.
Muller, M., de Vries, E. G., & Jansen, P. L. (1996). Role of multidrug resistance protein (MRP) in glutathione S-conjugate transport in mammalian cells. Journal of Hepatology, 24, 100–108.
Stride, B. D., Grant, C. E., Loe, D. W., Hipfner, D. R., Cole, S. P. C., & Deeley, R. G. (1997). Pharmacological characterization of the murine and human orthologs of multidrug-resistance protein in transfected human embryonic kidney cells. Molecular Pharmacology, 52, 344–353.
Gao, M., Loe, D. W., Grant, C. E., Cole, S. P. C., & Deeley, R. G. (1996). Reconstitution of ATP-dependent leukotriene C4 transport by co-expression of both half-molecules of human multidrug resistance protein in insect cells. Journal of Biological Chemistry, 271, 27782–27787.
Keppler, D., Leier, I., Jedlitschky, G., Mayer, R., & Buchler, M. (1996). The function of the multidrug resistance proteins (MRP and cMRP) in drug conjugate transport and hepatobiliary excretion. Advances in Enzyme Regulation, 36, 17–29.
Lautier, D., Canitrot, Y., Deeley, R. G., & Cole, S. P. (1996). Multidrug resistance mediated by the multidrug resistance protein (MRP) gene. Biochemical Pharmacology, 52, 967–977.
Ren, X. Q., Furukawa, T., Aoki, S., Nakajima, T., Sumizawa, T., Haraguchi, M., et al. (2001). Glutathione-dependent binding of a photoaffinity analog of agosterol A to the C-terminal half of human multidrug resistance protein. Journal of Biological Chemistry, 276, 23197–23206.
Payen, L., Gao, M., Westlake, C., Theis, A., Cole, S. P., & Deeley, R. G. (2005). Functional interactions between nucleotide binding domains and leukotriene C4 binding sites of multidrug resistance protein 1 (ABCC1). Molecular Pharmacology, 67, 1944–1953.
Payen, L. F., Gao, M., Westlake, C. J., Cole, S. P., & Deeley, R. G. (2003). Role of carboxylate residues adjacent to the conserved core Walker B motifs in the catalytic cycle of multidrug resistance protein 1 (ABCC1). Journal of Biological Chemistry, 278, 38537–38547.
Qian, Y. M., Qiu, W., Gao, M., Westlake, C. J., Cole, S. P., & Deeley, R. G. (2001). Characterization of binding of leukotriene C4 by human multidrug resistance protein 1: Evidence of differential interactions with NH2- and COOH-proximal halves of the protein. Journal of Biological Chemistry, 276, 38636–38644.
Karwatsky, J., Leimanis, M., Cai, J., Gros, P., & Georges, E. (2005). The leucotriene C4 binding sites in multidrug resistance protein 1 (ABCC1) include the first membrane multiple spanning domain. Biochemistry, 44, 340–351.
Daoud, R., Desneves, J., Deady, L. W., Tilley, L., Scheper, R. J., Gros, P., et al. (2000). The multidrug resistance protein is photoaffinity labeled by a quinoline-based drug at multiple sites. Biochemistry, 39, 6094–6102.
Daoud, R., Kast, C., Gros, P., & Georges, E. (2000). Rhodamine 123 binds to multiple sites in the multidrug resistance protein (MRP1). Biochemistry, 39, 15344–15352.
Qian, Y. M., Grant, C. E., Westlake, C. J., Zhang, D. W., Lander, P. A., Shepard, R. L., et al. (2002). Photolabeling of human and murine multidrug resistance protein 1 with the high affinity inhibitor [125I]LY475776 and azidophenacyl-[35S]glutathione. Journal of Biological Chemistry, 277, 35225–35231.
Mao, Q., Qiu, W., Weigl, K. E., Lander, P. A., Tabas, L. B., Shepard, R. L., et al. (2002). GSH-dependent photolabeling of multidrug resistance protein MRP1 (ABCC1) by [125I]LY475776. Evidence of a major binding site in the COOH-proximal membrane spanning domain. Journal of Biological Chemistry, 277, 28690–28699.
Daoud, R., Julien, M., Gros, P., & Georges, E. (2001). Major photoaffinity drug binding sites in multidrug resistance protein 1 (MRP1) are within transmembrane domains 10–11 and 16–17. Journal of Biological Chemistry, 276, 12324–12330.
Greenberger, L. M. (1993). Major photoaffinity drug labeling sites for iodoaryl azidoprazosin in P-glycoprotein are within, or immediately C-terminal to, transmembrane domains 6 and 12. Journal of Biological Chemistry, 268, 11417–11425.
Loo, T. W., & Clarke, D. M. (1997). Identification of residues in the drug-binding site of human P-glycoprotein using a thiol-reactive substrate. Journal of Biological Chemistry, 272, 31945–31948.
Dey, S., Ramachandra, M., Pastan, I., Gottesman, M. M., & Ambudkar, S. V. (1997). Evidence for two nonidentical drug-interaction sites in the human P-glycoprotein. Proceedings of the National Academy of Sciences of the United States of America, 94, 10594–10599.
Shapiro, A. B., Fox, K., Lam, P., & Ling, V. (1999). Stimulation of P-glycoprotein-mediated drug transport by prazosin and progesterone. Evidence for a third drug-binding site. European Journal of Biochemistry, 259, 841–850.
Leslie, E. M., Letourneau, I. J., Deeley, R. G., & Cole, S. P. (2003). Functional and structural consequences of cysteine substitutions in the NH2 proximal region of the human multidrug resistance protein 1 (MRP1/ABCC1). Biochemistry, 42, 5214–5224.
Koike, K., Conseil, G., Leslie, E. M., Deeley, R. G., & Cole, S. P. (2004). Identification of proline residues in the core cytoplasmic and transmembrane regions of multidrug resistance protein 1 (MRP1/ABCC1) important for transport function, substrate specificity, and nucleotide interactions. Journal of Biological Chemistry, 279, 12325–12336.
Haimeur, A., Deeley, R. G., & Cole, S. P. (2002). Charged amino acids in the sixth transmembrane helix of multidrug resistance protein 1 (MRP1/ABCC1) are critical determinants of transport activity. Journal of Biological Chemistry, 277, 41326–41333.
Koike, K., Oleschuk, C. J., Haimeur, A., Olsen, S. L., Deeley, R. G., & Cole, S. P. (2002). Multiple membrane-associated tryptophan residues contribute to the transport activity and substrate specificity of the human multidrug resistance protein, MRP1. Journal of Biological Chemistry, 277, 49495–49503.
Zhang, D. W., Nunoya, K., Vasa, M., Gu, H. M., Cole, S. P., & Deeley, R. G. (2006). Mutational analysis of polar amino acid residues within predicted transmembrane helices 10 and 16 of multidrug resistance protein 1 (ABCC1): Effect on substrate specificity. Drug Metabolism and Disposition, 34, 539–546.
Zhang, D. W., Nunoya, K., Vasa, M., Gu, H. M., Theis, A., Cole, S. P., et al. (2004). Transmembrane helix 11 of multidrug resistance protein 1 (MRP1/ABCC1): Identification of polar amino acids important for substrate specificity and binding of ATP at nucleotide binding domain 1. Biochemistry, 43, 9413–9425.
Campbell, J. D., Koike, K., Moreau, C., Sansom, M. S., Deeley, R. G., & Cole, S. P. (2004). Molecular modeling correctly predicts the functional importance of Phe594 in transmembrane helix 11 of the multidrug resistance protein, MRP1 (ABCC1). Journal of Biological Chemistry, 279, 463–468.
Zhang, D. W., Cole, S. P., & Deeley, R. G. (2001a). Identification of an amino acid residue in multidrug resistance protein 1 critical for conferring resistance to anthracyclines. Journal of Biological Chemistry, 276, 13231–13239.
Zhang, D. W., Gu, H. M., Situ, D., Haimeur, A., Cole, S. P., & Deeley, R. G. (2003). Functional importance of polar and charged amino acid residues in transmembrane helix 14 of multidrug resistance protein 1 (MRP1/ABCC1): Identification of an aspartate residue critical for conversion from a high to low affinity substrate binding state. Journal of Biological Chemistry, 278, 46052–46063.
Situ, D., Haimeur, A., Conseil, G., Sparks, K. E., Zhang, D., Deeley, R. G., et al. (2004). Mutational analysis of ionizable residues proximal to the cytoplasmic interface of membrane spanning domain 3 of the multidrug resistance protein, MRP1 (ABCC1): Glutamate 1204 is important for both the expression and catalytic activity of the transporter. Journal of Biological Chemistry, 279, 38871–38880.
Ito, K., Olsen, S. L., Qiu, W., Deeley, R. G., & Cole, S. P. (2001). Mutation of a single conserved tryptophan in multidrug resistance protein 1 (MRP1/ABCC1) results in loss of drug resistance and selective loss of organic anion transport. Journal of Biological Chemistry, 276, 15616–15624.
Zhang, D. W., Cole, S. P., & Deeley, R. G. (2001b). Identification of a nonconserved amino acid residue in multidrug resistance protein 1 important for determining substrate specificity: Evidence for functional interaction between transmembrane helices 14 and 17. Journal of Biological Chemistry, 276, 34966–34974.
Zhang, D. W., Cole, S. P., & Deeley, R. G. (2002). Determinants of the substrate specificity of multidrug resistance protein 1: Role of amino acid residues with hydrogen bonding potential in predicted transmembrane helix 17. Journal of Biological Chemistry, 277, 20934–20941.
Karwatsky, J., Daoud, R., Cai, J., Gros, P., & Georges, E. (2003). Binding of a photoaffinity analogue of glutathione to MRP1 (ABCC1) within two cytoplasmic regions (L0 and L1) as well as transmembrane domains 10–11 and 16–17. Biochemistry, 42, 3286–3294.
Karwatsky, J. M., & Georges, E. (2004). Drug binding domains of MRP1 (ABCC1) as revealed by photoaffinity labeling. Current Medicinal Chemistry. Anti-cancer Agents, 4, 19–30.
Gao, M., Yamazaki, M., Loe, D. W., Westlake, C. J., Grant, C. E., Cole, S. P. C., et al. (1998). Multidrug resistance protein—Identification of regions required for active transport of leukotriene C-4. Journal of Biological Chemistry, 273, 10733–10740.
Westlake, C. J., Qian, Y. M., Gao, M., Vasa, M., Cole, S. P., & Deeley, R. G. (2003). Identification of the structural and functional boundaries of the multidrug resistance protein 1 cytoplasmic loop 3. Biochemistry, 42, 14099–14113.
Bakos, E., Evers, R., Calenda, G., Tusnady, G. E., Szakacs, G., Varadi, A., et al. (2000). Characterization of the amino-terminal regions in the human multidrug resistance protein (MRP1). Journal of Cell Science, 113(Pt 24), 4451–4461.
Stride, B. D., Valdimarsson, G., Gerlach, J. H., Wilson, G. M., Cole, S. P., & Deeley, R. G. (1996). Structure and expression of the messenger RNA encoding the murine multidrug resistance protein, an ATP-binding cassette transporter. Molecular Pharmacology, 49, 962–971.
Stride, B. D., Cole, S. P., & Deeley, R. G. (1999). Localization of a substrate specificity domain in the multidrug resistance protein. Journal of Biological Chemistry, 274, 22877–22883.
Haimeur, A., Conseil, G., Deeley, R. G., & Cole, S. P. (2004). Mutations of charged amino acids in or near the transmembrane helices of the second membrane spanning domain differentially affect the substrate specificity and transport activity of the multidrug resistance protein MRP1 (ABCC1). Molecular Pharmacology, 65, 1375–1385.
Pakunlu, R. I., Cook, T. J., & Minko, T. (2003). Simultaneous modulation of multidrug resistance and antiapoptotic cellular defense by MDR1 and BCL-2 targeted antisense oligonucleotides enhances the anticancer efficacy of doxorubicin. Pharmaceutical Research, 20, 351–359.
Loo, T. W., & Clarke, D. M. (1996). Mutational analysis of the predicted first transmembrane segment of each homologous half of human P-glycoprotein suggests that they are symmetrically arranged in the membrane. Journal Biological Chemistry, 271, 15414–15419.
Allikmets, R., Schriml, L. M., Hutchinson, A., Romano-Spica, V., & Dean, M. (1998). A human placenta-specific ATP-binding cassette gene (ABCP) on chromosome 4q22 that is involved in multidrug resistance. Cancer Research, 58, 5337–5339.
Miyake, K., Mickley, L., Litman, T., Zhan, Z., Robey, R., Cristensen, B., et al. (1999). Molecular cloning of cDNAs which are highly overexpressed in mitoxantrone-resistant cells: Demonstration of homology to ABC transport genes. Cancer Research, 59, 8–13.
Doyle, L. A., Yang, W., Abruzzo, L. V., Krogmann, T., Gao, Y., Rishi, A. K., et al. (1998). A multidrug resistance transporter from human MCF-7 breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 95, 15665–15670.
Ozvegy, C., Varadi, A., & Sarkadi, B. (2002). Characterization of drug transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2 multidrug transporter. Modulation of substrate specificity by a point mutation. Journal of Biological Chemistry, 277, 47980–47990.
Kage, K., Tsukahara, S., Sugiyama, T., Asada, S., Ishikawa, E., Tsuruo, T., et al. (2002). Dominant-negative inhibition of breast cancer resistance protein as drug efflux pump through the inhibition of S-S dependent homodimerization. International Journal of Cancer, 97, 626–630.
Litman, T., Jensen, U., Hansen, A., Covitz, K. M., Zhan, Z., Fetsch, P., et al. (2002). Use of peptide antibodies to probe for the mitoxantrone resistance-associated protein MXR/BCRP/ABCP/ABCG2. Biochimica et Biophysica Acta, 1565, 6–16.
Han, B., & Zhang, J. T. (2004). Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2. Current Medicinal Chemistry. Anti-cancer Agents, 4, 31–42.
Georges, E., Tsuruo, T., & Ling, V. (1993). Topology of P-glycoprotein as determined by epitope mapping of MRK-16 monoclonal antibody. Journal of Biological Chemistry, 268, 1792–1798.
Smith, P. C., Karpowich, N., Millen, L., Moody, J. E., Rosen, J., Thomas, P. J., et al. (2002). ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Molecular Cell, 10, 139–149.
Chen, J., Lu, G., Lin, J., Davidson, A. L., & Quiocho, F. A. (2003). A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle. Molecular Cell, 12, 651–661.
Moody, J. E., Millen, L., Binns, D., Hunt, J. F., & Thomas, P. J. (2002). Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters. Journal of Biological Chemistry, 277, 21111–21114.
Verdon, G., Albers, S. V., Dijkstra, B. W., Driessen, A. J., & Thunnissen, A. M. (2003). Crystal structures of the ATPase subunit of the glucose ABC transporter from Sulfolobus solfataricus: Nucleotide-free and nucleotide-bound conformations. Journal of Molecular Biology, 330, 343–358.
Locher, K. P., Lee, A. T., & Rees, D. C. (2002). The E. coli BtuCD structure: A framework for ABC transporter architecture and mechanism. Science, 296, 1091–1098.
Rosenberg, M. F., Mao, Q., Holzenburg, A., Ford, R. C., Deeley, R. G., & Cole, S. P. (2001). The structure of the multidrug resistance protein 1 (MRP1/ABCC1). Crystallization and single-particle analysis. Journal of Bioliogical Chemistry, 276, 16076–16082.
Soszynski, M., Kaluzna, A., Rychlik, B., Sokal, A., & Bartosz, G. (1998). Radiation inactivation suggests that human multidrug resistance-associated protein 1 occurs as a dimer in the human erythrocyte membrane. Archives of Biochemistry and Biophysics, 354, 311–316.
Cool, R. H., Veenstra, M. K., van Klompenburg, W., Heyne, R. I., Muller, M., de Vries, E. G., et al. (2002). S-decyl-glutathione nonspecifically stimulates the ATPase activity of the nucleotide-binding domains of the human multidrug resistance-associated protein, MRP1 (ABCC1). European Journal of Biochemistry, 269, 3470–3478.
Kern, A., Felfoldi, F., Sarkadi, B., & Varadi, A. (2000). Expression and characterization of the N- and C-terminal ATP-binding domains of MRP1. Biochemical and Biophysical Research Communications, 273, 913–919.
Ramaen, O., Sizun, C., Pamlard, O., Jacquet, E., & Lallemand, J. Y. (2005). Attempts to characterize the NBD heterodimer of MRP1: Transient complex formation involves Gly771 of the ABC signature sequence but does not enhance the intrinsic ATPase activity. Biochemical Journal, 391, 481–490.
Ramaen, O., Leulliot, N., Sizun, C., Ulryck, N., Pamlard, O., Lallemand, J. Y., et al. (2006). Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site. Journal of Molecular Biology, 359, 940–949.
Szentpetery, Z., Sarkadi, B., Bakos, E., & Varadi, A. (2004). Functional studies on the MRP1 multidrug transporter: Characterization of ABC-signature mutant variants. Anticancer Research, 24, 449–455.
Szentpetery, Z., Kern, A., Liliom, K., Sarkadi, B., Varadi, A., & Bakos, E. (2004). The role of the conserved glycines of ATP-binding cassette signature motifs of MRP1 in the communication between the substrate-binding site and the catalytic centers. Journal of Biological Chemistry, 279, 41670–41678.
Ren, X. Q., Furukawa, T., Haraguchi, M., Sumizawa, T., Aoki, S., Kobayashi, M., et al. (2004). Function of the ABC signature sequences in the human multidrug resistance protein 1. Molecular Pharmacology, 65, 1536–1542.
Senior, A. E. (1998). Catalytic mechanism of P-glycoprotein. Acta Physiologica Scandinavica. Supplementum, 643, 213–218.
Senior, A. E., al-Shawi, M. K., & Urbatsch, I. L. (1998). ATPase activity of Chinese hamster P-glycoprotein. Methods in Enzymology, 292, 514–523.
Urbatsch, I. L., Sankaran, B., Weber, J., & Senior, A. E. (1995a). P-glycoprotein is stably inhibited by vanadate-induced trapping of nucleotide at a single catalytic site. Journal of Biological Chemistry, 270, 19383–19390.
Urbatsch, I. L., Sankaran, B., Bhagat, S., & Senior, A. E. (1995b). Both P-glycoprotein nucleotide-binding sites are catalytically active. Journal of Biological Chemistry, 270, 26956–26961.
Senior, A. E., & Bhagat, S. (1998). P-glycoprotein shows strong catalytic cooperativity between the two nucleotide sites. Biochemistry, 37, 831–836.
Carrier, I., Julien, M., & Gros, P. (2003). Analysis of catalytic carboxylate mutants E552Q and E1197Q suggests asymmetric ATP hydrolysis by the two nucleotide-binding domains of P-glycoprotein. Biochemistry, 42, 12875–12885.
Urbatsch, I. L., Beaudet, L., Carrier, I., & Gros, P. (1998). Mutations in either nucleotide-binding site of P-glycoprotein (Mdr3) prevent vanadate trapping of nucleotide at both sites. Biochemistry, 37, 4592–4602.
Urbatsch, I. L., Julien, M., Carrier, I., Rousseau, M. E., Cayrol, R., & Gros, P. (2000). Mutational analysis of conserved carboxylate residues in the nucleotide binding sites of P-glycoprotein. Biochemistry, 39, 14138–14149.
Azzaria, M., Schurr, E., & Gros, P. (1989). Discrete mutations introduced in the predicted nucleotide-binding sites of the mdr1 gene abolish its ability to confer multidrug resistance. Molecular and Cellular Biology, 9, 5289–5297.
Senior, A. E., al-Shawi, M. K., & Urbatsch, I. L. (1995). The catalytic cycle of P-glycoprotein. FEBS Letters, 377, 285–289.
Sauna, Z. E., & Ambudkar, S. V. (2000). Evidence for a requirement for ATP hydrolysis at two distinct steps during a single turnover of the catalytic cycle of human P-glycoprotein. Proceedings of the National Academy of Sciences of the United States of America, 97, 2515–2520.
Sauna, Z. E., & Ambudkar, S. V. (2001). Characterization of the catalytic cycle of ATP hydrolysis by human P- glycoprotein. The two ATP hydrolysis events in a single catalytic cycle are kinetically similar but affect different functional outcomes. Journal of Biological Chemistry, 276, 11653–11661.
Hrycyna, C. A., Ramachandra, M., Germann, U. A., Cheng, P. W., Pastan, I., & Gottesman, M. M. (1999). Both ATP sites of human P-glycoprotein are essential but not symmetric. Biochemistry, 38, 13887–13899.
Vigano, C., Julien, M., Carrier, I., Gros, P., & Ruysschaert, J. M. (2002). Structural and functional asymmetry of the nucleotide-binding domains of P-glycoprotein investigated by attenuated total reflection Fourier transform infrared spectroscopy. Journal of Biological Chemistry, 277, 5008–5016.
Beaudet, L., & Gros, P. (1995). Functional dissection of P-glycoprotein nucleotide-binding domains in chimeric and mutant proteins. Modulation of drug resistance profiles. Journal of Biological Chemistry, 270, 17159–17170.
Matsuo, M., Kioka, N., Amachi, T., & Ueda, K. (1999). ATP binding properties of the nucleotide-binding folds of SUR1. Journal of Biological Chemistry, 274, 37479–37482.
Matsuo, M., Tanabe, K., Kioka, N., Amachi, T., & Ueda, K. (2000). Different binding properties and affinities for ATP and ADP among sulfonylurea receptor subtypes, SUR1, SUR2A, and SUR2B. Journal of Biological Chemistry, 275, 28757–28763.
Szabo, K., Szakacs, G., Hegeds, T., & Sarkadi, B. (1999). Nucleotide occlusion in the human cystic fibrosis transmembrane conductance regulator. Different patterns in the two nucleotide binding domains. Journal of Biological Chemistry, 274, 12209–12212.
Aleksandrov, L., Mengos, A., Chang, X. B., Aleksandrov, A., & Riordan, J. R. (2001). Differential interactions of nucleotides at the two nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator. Journal of Biological Chemistry, 276, 12918–12923.
Aleksandrov, L., Aleksandrov, A. A., Chang, X. B., & Riordan, J. R. (2002). The first nucleotide binding domain of cystic fibrosis transmembrane conductance regulator is a site of stable nucleotide interaction, whereas the second is a site of rapid turnover. Journal of Biological Chemistry, 277, 15419–15425.
Cui, L., Hou, Y. X., Riordan, J. R., & Chang, X. B. (2001). Mutations of the Walker B motif in the first nucleotide binding domain of multidrug resistance protein MRP1 prevent conformational maturation. Archives of Biochemistry and Biophysics, 392, 153–161.
Nagata, K., Nishitani, M., Matsuo, M., Kioka, N., Amachi, T., & Ueda, K. (2000). Nonequivalent nucleotide trapping in the two nucleotide binding folds of the human multidrug resistance protein MRP1. Journal of Biological Chemistry, 275, 17626–17630.
Hou, Y. X., Cui, L., Riordan, J. R., & Chang, X. B. (2002). ATP binding to the first nucleotide-binding domain of multidrug resistance protein MRP1 increases binding and hydrolysis of ATP and trapping of ADP at the second domain. Journal of Biological Chemistry, 277, 5110–5119.
Hou, Y. X., Riordan, J. R., & Chang, X. B. (2003). ATP binding, not hydrolysis, at the first nucleotide-binding domain of multidrug resistance-associated protein MRP1 enhances ADP.Vi trapping at the second domain. Journal of Biological Chemistry, 278, 3599–3605.
Yang, R., Cui, L., Hou, Y.-X., Riordan, J. R., & Chang, X. B. (2003). ATP binding to the first nucleotide binding domain of multidrug resistance-associated protein plays a regulatory role at low nucleotide concentration, whereas ATP hydrolysis at the second plays a dominant role in ATP-dependent leukotriene C4 transport. Journal of Biological Chemistry, 278, 30764–30771.
Yang, R., McBride, A., Hou, Y. X., Goldberg, A., & Chang, X. B. (2005). Nucleotide dissociation from NBD1 promotes solute transport by MRP1. Biochimica et Biophysica Acta, 1668, 248–261.
Taguchi, Y., Yoshida, A., Takada, Y., Komano, T., & Ueda, K. (1997). Anti-cancer drugs and glutathione stimulate vanadate-induced trapping of nucleotide in multidrug resistance-associated protein (MRP). FEBS Letters, 401, 11–14.
Mao, Q., Leslie, E. M., Deeley, R. G., & Cole, S. P. (1999). ATPase activity of purified and reconstituted multidrug resistance protein MRP1 from drug-selected H69AR cells. Biochimica et Biophysica Acta, 1461, 69–82.
Manciu, L., Chang, X. B., Riordan, J. R., Buyse, F., & Ruysschaert, J. M. (2001). Nucleotide-induced conformational changes in the human multidrug resistance protein MRP1 are related to the capacity of chemotherapeutic drugs to accumulate or not in resistant cells. FEBS Letters, 493, 31–35.
Buyse, F., Hou, Y. X., Vigano, C., Zhao, Q., Ruysschaert, J. M., & Chang, X. B. (2006). Replacement of the positively charged Walker A lysine residue with a hydrophobic leucine residue and conformational alterations caused by this mutation in MRP1 impair ATP binding and hydrolysis. Biochemical Journal, 397, 121–130.
Manciu, L., Chang, X. B., Riordan, J. R., & Ruysschaert, J. M. (2000). Multidrug resistance protein MRP1 reconstituted into lipid vesicles: Secondary structure and nucleotide-induced tertiary structure changes. Biochemistry, 39, 13026–13033.
Smith, M. R., Jin, F., & Joshi, I. (2004). Enhanced efficacy of therapy with antisense BCL-2 oligonucleotides plus anti-CD20 monoclonal antibody in scid mouse/human lymphoma xenografts. Molecular Cancer Therapeutics, 3, 1693–1699.
Ramaen, O., Masscheleyn, S., Duffieux, F., Pamlard, O., Oberkampf, M., Lallemand, J. Y., et al. (2003). Biochemical characterization and NMR studies of the nucleotide-binding domain 1 of multidrug-resistance-associated protein 1: Evidence for interaction between ATP and Trp653. Biochemical Journal, 376, 749–756.
Zhao, Q., & Chang, X. B. (2004). Mutation of the aromatic amino acid interacting with adenine moiety of ATP to a polar residue alters the properties of multidrug resistance protein 1. Journal of Biological Chemistry, 279, 48505–48512.
Flens, M. J., Zaman, G. J., van der Valk, P., Izquierdo, M. A., Schroeijers, A. B., Scheffer, G. L., et al. (1996). Tissue distribution of the multidrug resistance protein. American Journal of Pathology, 148, 1237–1247.
St-Pierre, M. V., Serrano, M. A., Macias, R. I., Dubs, U., Hoechli, M., Lauper, U., et al. (2000). Expression of members of the multidrug resistance protein family in human term placenta. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 279, R1495–R1503.
Zaman, G. J., Versantvoort, C. H., Smit, J. J., Eijdems, E. W., de Haas, M., Smith, A. J., et al. (1993). Analysis of the expression of MRP, the gene for a new putative transmembrane drug transporter, in human multidrug resistant lung cancer cell lines. Cancer Research, 53, 1747–1750.
Nishino, J., Suzuki, H., Sugiyama, D., Kitazawa, T., Ito, K., Hanano, M., et al. (1999). Transepithelial transport of organic anions across the choroid plexus: Possible involvement of organic anion transporter and multidrug resistance-associated protein. Journal of Pharmacology and Experimental Therapeutics, 290, 289–294.
Choudhuri, S., Cherrington, N. J., Li, N., & Klaassen, C. D. (2003). Constitutive expression of various xenobiotic and endobiotic transporter mRNAs in the choroid plexus of rats. Drug Metabolism and Disposition, 31, 1337–1345.
Atkinson, D. E., Greenwood, S. L., Sibley, C. P., Glazier, J. D., & Fairbairn, L. J. (2003). Role of MDR1 and MRP1 in trophoblast cells, elucidated using retroviral gene transfer. American Journal of Physiology. Cell Physiology, 285, C584–C591.
Brechot, J. M., Hurbain, I., Fajac, A., Daty, N., & Bernaudin, J. F. (1998). Different pattern of MRP localization in ciliated and basal cells from human bronchial epithelium. Journal of Histochemistry and Cytochemistry, 46, 513–517.
Lohoff, M., Prechtl, S., Sommer, F., Roellinghoff, M., Schmitt, E., Gradehandt, G., et al. (1998). A multidrug-resistance protein (MRP)-like transmembrane pump is highly expressed by resting murine T helper (Th) 2, but not Th1 cells, and is induced to equal expression levels in Th1 and Th2 cells after antigenic stimulation in vivo. Journal of Clinical Investigation, 101, 703–710.
Leslie, E. M., Deeley, R. G., & Cole, S. P. (2005). Multidrug resistance proteins: Role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicology and Applied Pharmacology, 204, 216–237.
Nagashige, M., Ushigome, F., Koyabu, N., Hirata, K., Kawabuchi, M., Hirakawa, T., et al. (2003). Basal membrane localization of MRP1 in human placental trophoblast. Placenta, 24, 951–958.
Pascolo, L., Fernetti, C., Pirulli, D., Crovella, S., Amoroso, A., & Tiribelli, C. (2003). Effects of maturation on RNA transcription and protein expression of four MRP genes in human placenta and in BeWo cells. Biochemical and Biophysical Research Communications, 303, 259–265.
Peng, K. C., Cluzeaud, F., Bens, M., Van Huyen, J. P., Wioland, M. A., Lacave, R., et al. (1999). Tissue and cell distribution of the multidrug resistance-associated protein (MRP) in mouse intestine and kidney. Journal of Histochemistry and Cytochemistry, 47, 757–768.
St-Pierre, M. V., Stallmach, T., Freimoser Grundschober, A., Dufour, J. F., Serrano, M. A., Marin, J. J., et al. (2004). Temporal expression profiles of organic anion transport proteins in placenta and fetal liver of the rat. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology, 287, R1505–R1516.
Tribull, T. E., Bruner, R. H., & Bain, L. J. (2003). The multidrug resistance-associated protein 1 transports methoxychlor and protects the seminiferous epithelium from injury. Toxicology Letters, 142, 61–70.
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.
Wright, S. R., Boag, A. H., Valdimarsson, G., Hipfner, D. R., Campling, B. G., Cole, S. P., et al. (1998). Immunohistochemical detection of multidrug resistance protein in human lung cancer and normal lung. Clinical Cancer Research, 4, 2279–2289.
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.
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.
Mercier, C., Masseguin, C., Roux, F., Gabrion, J., & Scherrmann, J. M. (2004). Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: Focus on astrocytes. Brain Research, 1021, 32–40.
de Lange, E. C. (2004). Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Advanced Drug Delivery Reviews, 56, 1793–1809.
Bart, J., Hollema, H., Groen, H. J., de Vries, E. G., Hendrikse, N. H., Sleijfer, D. T., et al. (2004). The distribution of drug-efflux pumps, P-gp, BCRP, MRP1 and MRP2, in the normal blood-testis barrier and in primary testicular tumours. European Journal of Cancer, 40, 2064–2070.
Cha, S. H., Sekine, T., Fukushima, J. I., Kanai, Y., Kobayashi, Y., Goya, T., et al. (2001). Identification and characterization of human organic anion transporter 3 expressing predominantly in the kidney. Molecular Pharmacology, 59, 1277–1286.
Schaub, T. P., Kartenbeck, J., Konig, J., Spring, H., Dorsam, J., Staehler, G., et al. (1999). Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. Journal of the American Society of Nephrology, 10, 1159–1169.
Evers, R., Zaman, G. J., van Deemter, L., Jansen, H., Calafat, J., Oomen, L. C., et al. (1996). Basolateral localization and export activity of the human multidrug resistance-associated protein in polarized pig kidney cells. Journal of Clinical Investigation, 97, 1211–1218.
Hipfner, D. R., Gauldie, S. D., Deeley, R. G., & Cole, S. P. (1994). Detection of the M(r) 190,000 multidrug resistance protein, MRP, with monoclonal antibodies. Cancer Research, 54, 5788–5792.
Roelofsen, H., Vos, T. A., Schippers, I. J., Kuipers, F., Koning, H., Moshage, H., et al. (1997). Increased levels of the multidrug resistance protein in lateral membranes of proliferating hepatocyte-derived cells. Gastroenterology, 112, 511–521.
Thiebaut, F., Tsuruo, T., Hamada, H., Gottesman, M. M., Pastan, I., & Willingham, M. C. (1987). Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proceedings of the National Academy of Sciences of the United States of America, 84, 7735–7738.
Kartenbeck, J., Leuschner, U., Mayer, R., & Keppler, D. (1996). Absence of the canalicular isoform of the MRP gene-encoded conjugate export pump from the hepatocytes in Dubin–Johnson syndrome. Hepatology, 23, 1061–1066.
Maliepaard, M., Scheffer, G. L., Faneyte, I. F., van Gastelen, M. A., Pijnenborg, A. C., Schinkel, A. H., et al. (2001). Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Research, 61, 3458–3464.
Hoogeveen, A. T., Keulemans, J., Willemsen, R., Scholte, B. J., Bijman, J., Edixhoven, M. J., et al. (1991). Immunological localization of cystic fibrosis candidate gene products. Experimental Cell Research, 193, 435–437.
Marino, C. R., Matovcik, L. M., Gorelick, F. S., & Cohn, J. A. (1991). Localization of the cystic fibrosis transmembrane conductance regulator in pancreas. Journal of Clinical Investigation, 88, 712–716.
Crawford, I., Maloney, P. C., Zeitlin, P. L., Guggino, W. B., Hyde, S. C., Turley, H., et al. (1991). Immunocytochemical localization of the cystic fibrosis gene product CFTR. Proceedings of the National Academy of Sciences of the United States of America, 88, 9262–9266.
Sparreboom, A., van Asperen, J., Mayer, U., Schinkel, A. H., Smit, J. W., Meijer, D. K., et al. (1997). Limited oral bioavailability and active epithelial excretion of paclitaxel (Taxol) caused by P-glycoprotein in the intestine. Proceedings of the National Academy of Sciences of the United States of America, 94, 2031–2035.
Lankas, G. R., Wise, L. D., Cartwright, M. E., Pippert, T., & Umbenhauer, D. R. (1998). Placental P-glycoprotein deficiency enhances susceptibility to chemically induced birth defects in mice. Reproductive Toxicology, 12, 457–463.
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.
Rappa, G., Finch, R. A., Sartorelli, A. C., & Lorico, A. (1999). New insights into the biology and pharmacology of the multidrug resistance protein (MRP) from gene knockout models. Biochemical Pharmacology, 58, 557–562.
Rao, V. V., Dahlheimer, J. L., Bardgett, M. E., Snyder, A. Z., Finch, R. A., Sartorelli, A. C., et al. (1999). Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood-cerebrospinal-fluid drug-permeability barrier. Proceedings of the National Academy of Sciences of the United States of America, 96, 3900–3905.
Mayatepek, E. (2000). Leukotriene C4 synthesis deficiency: A member of a probably underdiagnosed new group of neurometabolic diseases. European Journal of Pediatrics, 159, 811–818.
Scoggan, K. A., Jakobsson, P. J., & Ford-Hutchinson, A. W. (1997). Production of leukotriene C4 in different human tissues is attributable to distinct membrane bound biosynthetic enzymes. Journal Biological Chemistry, 272, 10182–10187.
Schroder, O., Sjostrom, M., Qiu, H., Jakobsson, P. J., & Haeggstrom, J. Z. (2005). Microsomal glutathione S-transferases: Selective up-regulation of leukotriene C4 synthase during lipopolysaccharide-induced pyresis. Cellular and Molecular Life Sciences, 62, 87–94.
Shimada, K., Navarro, J., Goeger, D. E., Mustafa, S. B., Weigel, P. H., & Weinman, S. A. (1998). Expression and regulation of leukotriene-synthesis enzymes in rat liver cells. Hepatology, 28, 1275–1281.
Dekkers, D. W., Comfurius, P., Schroit, A. J., Bevers, E. M., & Zwaal, R. F. (1998). Transbilayer movement of NBD-labeled phospholipids in red blood cell membranes: Outward-directed transport by the multidrug resistance protein 1 (MRP1). Biochemistry, 37, 14833–14837.
Borst, P., Zelcer, N., & van Helvoort, A. (2000). ABC transporters in lipid transport. Biochimica et Biophysica Acta, 1486, 128–144.
Dekkers, D. W., Comfurius, P., van Gool, R. G., Bevers, E. M., & Zwaal, R. F. (2000). Multidrug resistance protein 1 regulates lipid asymmetry in erythrocyte membranes. Biochemical Journal, 350(Pt 2), 531–535.
Raggers, R. J., van Helvoort, A., Evers, R., & van Meer, G. (1999). The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane. Journal of Cell Science, 112(Pt 3), 415–422.
Mannechez, A., Collet, B., Payen, L., Lecureur, V., Fardel, O., Le Moyec, L., et al. (2001). Differentiation of the P-gp and MRP1 multidrug resistance systems by mobile lipid 1H-NMR spectroscopy and phosphatidylserine externalization. Anticancer Research, 21, 3915–3919.
Kamp, D., & Haest, C. W. (1998). Evidence for a role of the multidrug resistance protein (MRP) in the outward translocation of NBD-phospholipids in the erythrocyte membrane. Biochimica et Biophysica Acta, 1372, 91–101.
Sohnius, A., Kamp, D., & Haest, C. W. (2003). ATP and GSH dependence of MRP1-mediated outward translocation of phospholipid analogs in the human erythrocyte membrane. Molecular Membrane Biology, 20, 299–305.
Huang, Z., Chang, X., Riordan, J. R., & Huang, Y. (2004). Fluorescent modified phosphatidylcholine floppase activity of reconstituted multidrug resistance-associated protein MRP1. Biochimica et Biophysica Acta, 1660, 155–163.
Kruh, G. D., Chan, A., Myers, K., Gaughan, K., Miki, T., & Aaronson, S. A. (1994). Expression complementary DNA library transfer establishes mrp as a multidrug resistance gene. Cancer Research, 54, 1649–1652.
Breuninger, L. M., Paul, S., Gaughan, K., Miki, T., Chan, A., Aaronson, S. A., et al. (1995). Expression of multidrug resistance-associated protein in NIH/3T3 cells confers multidrug resistance associated with increased drug efflux and altered intracellular drug distribution. Cancer Research, 55, 5342–5347.
Schneider, E., Horton, J. K., Yang, C. H., Nakagawa, M., & Cowan, K. H. (1994). 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 Research, 54, 152–158.
Zijlstra, J. G., de Vries, E. G., & Mulder, N. H. (1987). Multifactorial drug resistance in an adriamycin-resistant human small cell lung carcinoma cell line. Cancer Research, 47, 1780–1784.
Eijdems, E. W., De Haas, M., Coco-Martin, J. M., Ottenheim, C. P., Zaman, G. J., Dauwerse, H. G., et al. (1995). Mechanisms of MRP over-expression in four human lung-cancer cell lines and analysis of the MRP amplicon. International Journal of Cancer, 60, 676–684.
Coley, H. M., Workman, P., & Twentyman, P. R. (1991). Retention of activity by selected anthracyclines in a multidrug resistant human large cell lung carcinoma line without P-glycoprotein hyperexpression. Bristish Journal of Cancer, 63, 351–357.
Versantvoort, C. H., Broxterman, H. J., Pinedo, H. M., de Vries, E. G., Feller, N., Kuiper, C. M., et al. (1992). Energy-dependent processes involved in reduced drug accumulation in multidrug-resistant human lung cancer cell lines without P-glycoprotein expression. Cancer Research, 52, 17–23.
van Triest, B., Pinedo, H. M., Telleman, F., van der Wilt, C. L., Jansen, G., & Peters, G. J. (1997). Cross-resistance to antifolates in multidrug resistant cell lines with P-glycoprotein or multidrug resistance protein expression. Biochemical Pharmacology, 53, 1855–1866.
Flens, M. J., Scheffer, G. L., van der Valk, P., Broxterman, H. J., Eijdems, E. W., Huysmans, A. C., et al. (1997). Identification of novel drug resistance-associated proteins by a panel of rat monoclonal antibodies. International Journal of Cancer, 73, 249–257.
Politi, P. M., & Sinha, B. K. (1989). Role of differential drug uptake, efflux, and binding of etoposide in sensitive and resistant human tumor cell lines: Implications for the mechanisms of drug resistance. Molecular Pharmacology, 35, 271–278.
Gillet, J. P., Efferth, T., Steinbach, D., Hamels, J., de Longueville, F., Bertholet, V., et al. (2004). Microarray-based detection of multidrug resistance in human tumor cells by expression profiling of ATP-binding cassette transporter genes. Cancer Research, 64, 8987–8993.
Slovak, M. L., Hoeltge, G. A., Dalton, W. S., & Trent, J. M. (1988). Pharmacological and biological evidence for differing mechanisms of doxorubicin resistance in two human tumor cell lines. Cancer Research, 48, 2793–2797.
Denoyer, D., Perek, N., Le Jeune, N., Frere, D., & Dubois, F. (2003). The multidrug resistance of in vitro tumor cell lines derived from human breast carcinoma MCF-7 does not influence pentavalent technetium-99m-dimercaptosuccinic Acid uptake. Cancer Biotherapy & Radiopharmaceuticals, 18, 791–801.
Sumizawa, T., Chuman, Y., Sakamoto, H., Iemura, K., Almquist, K. C., Deeley, R. G., et al. (1994). Non-P-glycoprotein-mediated multidrug-resistant human KB cells selected in medium containing adriamycin, cepharanthine, and mezerein. Somatic Cell and Molecular Genetics, 20, 423–435.
Chauvier, D., Morjani, H., & Manfait, M. (2002). Homocamptothecin-daunorubicin association overcomes multidrug-resistance in breast cancer MCF7 cells. Breast Cancer Research and Treatment, 73, 113–125.
Larkin, A., O’Driscoll, L., Kennedy, S., Purcell, R., Moran, E., Crown, J., et al. (2004). Investigation of MRP-1 protein and MDR-1 P-glycoprotein expression in invasive breast cancer: A prognostic study. International Journal of Cancer, 112, 286–294.
Rybarova, S., Hodorova, I., Hajdukova, M., Schmidtova, K., Mojzis, J., Kajo, K., et al. (2006). Expression of MDR proteins in breast cancer and its correlation with some clinical and pathological parameters. Neoplasma, 53, 128–135.
Burger, H., Foekens, J. A., Look, M. P., Meijer-van Gelder, M. E., Klijn, J. G., Wiemer, E. A., et al. (2003). RNA expression of breast cancer resistance protein, lung resistance-related protein, multidrug resistance-associated proteins 1 and 2, and multidrug resistance gene 1 in breast cancer: Correlation with chemotherapeutic response. Clinical Cancer Research, 9, 827–836.
Nooter, K., Brutel de la Riviere, G., Look, M. P., van Wingerden, K. E., Henzen-Logmans, S. C., Scheper, R. J., et al. (1997). The prognostic significance of expression of the multidrug resistance-associated protein (MRP) in primary breast cancer. British Journal of Cancer, 76, 486–493.
Charpin, C., Vielh, P., Duffaud, F., Devictor, B., Andrac, L., Lavaut, M. N., et al. (1994). Quantitative immunocytochemical assays of P-glycoprotein in breast carcinomas: Correlation to messenger RNA expression and to immunohistochemical prognostic indicators. Journal of the National Cancer Institute, 86, 1539–1545.
Filipits, M., Suchomel, R. W., Dekan, G., Haider, K., Valdimarsson, G., Depisch, D., et al. (1996). MRP and MDR1 gene expression in primary breast carcinomas. Clinical Cancer Research, 2, 1231–1237.
Rudas, M., Filipits, M., Taucher, S., Stranzl, T., Steger, G. G., Jakesz, R., et al. (2003). Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. Breast Cancer Research and Treatment, 81, 149–157.
Cole, S. P., Downes, H. F., Mirski, S. E., & Clements, D. J. (1990). Alterations in glutathione and glutathione-related enzymes in a multidrug-resistant small cell lung cancer cell line. Molecular Pharmacology, 37, 192–197.
Campling, B. G., Baer, K., Baker, H. M., Lam, Y. M., & Cole, S. P. (1993). Do glutathione and related enzymes play a role in drug resistance in small cell lung cancer cell lines? British Journal of Cancer, 68, 327–335.
Rappa, G., Gamcsik, M. P., Mitina, R. L., Baum, C., Fodstad, O., & Lorico, A. (2003). Retroviral transfer of MRP1 and gamma-glutamyl cysteine synthetase modulates cell sensitivity to L-buthionine-S,R-sulphoximine (BSO): New rationale for the use of BSO in cancer therapy. European Journal of Cancer, 39, 120–128.
Schneider, E., Yamazaki, H., Sinha, B. K., & Cowan, K. H. (1995). Buthionine sulphoximine-mediated sensitisation of etoposide-resistant human breast cancer MCF7 cells overexpressing the multidrug resistance- associated protein involves increased drug accumulation. British Journal of Cancer, 71, 738–743.
Versantvoort, C. H., Broxterman, H. J., Bagrij, T., Scheper, R. J., & Twentyman, P. R. (1995). Regulation by glutathione of drug transport in multidrug-resistant human lung tumour cell lines overexpressing multidrug resistance- associated protein. British Journal of Cancer, 72, 82–89.
Zaman, G. J., Lankelma, J., van Tellingen, O., Beijnen, J., Dekker, H., Paulusma, C., et al. (1995). Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein. Proceedings of the National Academy of Sciences of the United States of America, 92, 7690–7694.
Benlloch, M., Ortega, A., Ferrer, P., Segarra, R., Obrador, E., Asensi, M., et al. (2005). Acceleration of glutathione efflux and inhibition of gamma-glutamyltranspeptidase sensitize metastatic B16 melanoma cells to endothelium-induced cytotoxicity. Journal of Biological Chemistry, 280, 6950–6959.
Rappa, G., Lorico, A., Flavell, R. A., & Sartorelli, A. C. (1997). Evidence that the multidrug resistance protein (MRP) functions as a co-transporter of glutathione and natural product toxins. Cancer Research, 57, 5232–5237.
Leslie, E. M., Haimeur, A., & Waalkes, M. P. (2004). Arsenic transport by the human multidrug resistance protein 1 (MRP1/ABCC1). Evidence that a tri-glutathione conjugate is required. Journal of Biological Chemistry, 279, 32700–32708.
Trompier, D., Chang, X. B., Barattin, R., du Moulinet D’Hardemare, A., Di Pietro, A., & Baubichon-Cortay, H. (2004). Verapamil and its derivative trigger apoptosis through glutathione extrusion by multidrug resistance protein MRP1. Cancer Research, 64, 4950–4956.
Majumder, S., Dutta, P., Mookerjee, A., & Choudhuri, S. K. (2006). The role of a novel copper complex in overcoming doxorubicin resistance in Ehrlich ascites carcinoma cells in vivo. Chemico-biological Interactions, 159, 90–103.
Salerno, M., Loechariyakul, P., Saengkhae, C., & Garnier-Suillerot, A. (2004). Relation between the ability of some compounds to modulate the MRP1-mediated efflux of glutathione and to inhibit the MRPl-mediated efflux of daunorubicin. Biochemical Pharmacology, 68, 2159–2165.
Hu, K., & Morris, M. E. (2004). Effects of benzyl-, phenethyl-, and alpha-naphthyl isothiocyanates on P-glycoprotein- and MRP1-mediated transport. Journal of Pharmaceutical Sciences, 93, 1901–1911.
Gekeler, V., Ise, W., Sanders, K. H., Ulrich, W. R., & Beck, J. (1995). The leukotriene LTD4 receptor antagonist MK571 specifically modulates MRP associated multidrug resistance. Biochemical and Biophysical Research Communications, 208, 345–352.
Vanhoefer, U., Cao, S., Minderman, H., Toth, K., Skenderis, B. S. 2nd, Slovak, M. L., et al. (1996). d,l-buthionine-(S,R)-sulfoximine potentiates in vivo the therapeutic efficacy of doxorubicin against multidrug resistance protein-expressing tumors. Clinical Cancer Research, 2, 1961–1968.
Seo, T., Urasaki, Y., Takemura, H., & Ueda, T. (2005). Arsenic trioxide circumvents multidrug resistance based on different mechanisms in human leukemia cell lines. Anticancer Research, 25, 991–998.
Akan, I., Akan, S., Akca, H., Savas, B., & Ozben, T. (2005). Multidrug resistance-associated protein 1 (MRP1) mediated vincristine resistance: Effects of N-acetylcysteine and Buthionine sulfoximine. Cancer Cell International, 5, 22.
Akan, I., Akan, S., Akca, H., Savas, B., & Ozben, T. (2004). N-acetylcysteine enhances multidrug resistance-associated protein 1 mediated doxorubicin resistance. European Journal of Clinical Investigation, 34, 683–689.
Benderra, Z., Trussardi, A., Morjani, H., Villa, A. M., Doglia, S. M., & Manfait, M. (2000). Regulation of cellular glutathione modulates nuclear accumulation of daunorubicin in human MCF7 cells overexpressing multidrug resistance associated protein. European Journal of Cancer, 30, 428–434.
Le Jeune, N., Perek, N., Denoyer, D., & Dubois, F. (2004). Influence of glutathione depletion on plasma membrane cholesterol esterification and on Tc-99m-sestamibi and Tc-99m-tetrofosmin uptakes: A comparative study in sensitive U-87-MG and multidrug-resistant MRP1 human glioma cells. Cancer Biotherapy & Radiopharmaceuticals, 19, 411–421.
Perek, N., Koumanov, F., Denoyer, D., Boudard, D., & Dubois, F. (2002). Modulation of the multidrug resistance of glioma by glutathione levels depletion-interaction with Tc-99M-Sestamibi and Tc-99M-Tetrofosmin. Cancer Biotherapy & Radiopharmaceuticals, 17, 291–302.
Sharp, S. Y., Smith, V., Hobbs, S., & Kelland, L. R. (1998). Lack of a role for MRP1 in platinum drug resistance in human ovarian cancer cell lines. British Journal of Cancer, 78, 175–180.
Chuman, Y., Chen, Z. S., Seto, K., Sumizawa, T., Furukawa, T., Tani, A., et al. (1998). Reversal of MRP-mediated vincristine resistance in KB cells by buthionine sulfoximine in combination with PAK-104P. Cancer Letter, 129, 69–76.
Buchler, M., Konig, J., Brom, M., Kartenbeck, J., Spring, H., Horie, T., et al. (1996). cDNA cloning of the hepatocyte canalicular isoform of the multidrug resistance protein, cMrp, reveals a novel conjugate export pump deficient in hyperbilirubinemic mutant rats. Journal of Biological Chemistry, 271, 15091–15098.
Paulusma, C. C., Bosma, P. J., Zaman, G. J., Bakker, C. T., Otter, M., Scheffer, G. L., et al. (1996). Congenital jaundice in rats with a mutation in a multidrug resistance-associated protein gene. Science, 271, 1126–1128.
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.
Kool, M., van der Linden, M., de Haas, M., Baas, F., & Borst, P. (1999). Expression of human MRP6, a homologue of the multidrug resistance protein gene MRP1, in tissues and cancer cells. Cancer Research, 59, 175–182.
Hopper, E., Belinsky, M. G., Zeng, H., Tosolini, A., Testa, J. R., & Kruh, G. D. (2001). Analysis of the structure and expression pattern of MRP7 (ABCC10), a new member of the MRP subfamily. Cancer Letter, 162, 181–191.
Bera, T. K., Lee, S., Salvatore, G., Lee, B., & Pastan, I. (2001). MRP8, a new member of ABC transporter superfamily, identified by EST database mining and gene prediction program, is highly expressed in breast cancer. Molecular Medicine, 7, 509–516.
Tammur, J., Prades, C., Arnould, I., Rzhetsky, A., Hutchinson, A., Adachi, M., et al. (2001). Two new genes from the human ATP-binding cassette transporter superfamily, ABCC11 and ABCC12, tandemly duplicated on chromosome 16q12. Gene, 273, 89–96.
Yabuuchi, H., Takayanagi, S., Yoshinaga, K., Taniguchi, N., Aburatani, H., & Ishikawa, T. (2002). ABCC13, an unusual truncated ABC transporter, is highly expressed in fetal human liver. Biochemical and Biophysical Research Communications, 299, 410–417.
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Chang, Xb. A molecular understanding of ATP-dependent solute transport by multidrug resistance-associated protein MRP1. Cancer Metastasis Rev 26, 15–37 (2007). https://doi.org/10.1007/s10555-007-9041-7
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DOI: https://doi.org/10.1007/s10555-007-9041-7