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Transport of Glutathione, Glucuronate, and Sulfate Conjugates by the MRP Gene-encoded Conjugate Export Pump¹

Division of Tumor Biochemistry, Deutsches Krebsforschungszentrum, In Neuenheimer Feld 280, D-69120 Heidelberg, Germany [G. J., I. L., U. B., K. B., D. K.] and Department for Organic Chemistry and Biochemistry, University of Freiburg, D-79104 Freiburg, Germany [G. K.]

Previous studies have identified the ATP-dependent export of glutathione conjugates as a physiological function of the multidrug resistance protein (MRP). The involvement of MRP in the transport of endogenous and xenobiotic conjugates was investigated further using membrane vesicles from MRP-transfected HeLa cells. The ATP-dependent transport of the glutathione conjugates [³H]leukotriene C₄, S-(2,4-dinitrophenyl)-[³H]glutathione, and ³H-labeled oxidized glutathione was characterized by determination of the transport efficiency V_max:K_m amounting to 1031, 114, and 7.1 ml x mg protein^-1 x min^-1, respectively. Additional endogenous substrates for MRP-mediated transport included the steroid conjugate 17ß-glucuronosyl [³H]estradiol and the bile salt conjugates [6-¹⁴C]glucuronosylhyodeoxycholate and 3-sulfatolithocholyl [³H]taurine. The K_m value of MRP for 17ß-glucuronosyl [³H]estradiol was 1.5 ± 0.3 µM, with a V_max:K_m ratio of 42 ml x mg protein^-1 x min^-1, and a K_i value of 0.7 µM for the leukotriene receptor antagonist MK 571. MRP-mediated ATP-dependent transport was observed for the anticancer drug conjugates glucuronosyl [³H]etoposide and monochloro-mono[³H]glutathionyl melphalan, but not for unmodified [¹⁴C]doxorubicin, [³H]daunorubicin, or [³H]vinblastine. Our results establish that MRP functions as an ATP-dependent export pump not only for glutathione conjugates but also for glucuronidated and sulfated endogenous as well as exogenous compounds.

¹ This work was supported in part by the Deutsche Forschungsgemeinschaft through SFB 352 (Heidelberg, Germany).

² To whom requests for reprints should be addressed. Phone: +49/6221-422404; Fax: +49/6221-422402.

Received 11/ 1/95. Accepted 1/ 4/96.

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				M. L. O'Brien, B. Vulevic, S. Freer, J. Boyd, H. Shen, and K. D. Tew Glutathione Peptidomimetic Drug Modulator of Multidrug Resistance-Associated Protein J. Pharmacol. Exp. Ther., December 1, 1999; 291(3): 1348 - 1355. [Abstract] [Full Text]

				U.K. Walle and T. Walle Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps Carcinogenesis, November 1, 1999; 20(11): 2153 - 2157. [Abstract] [Full Text] [PDF]

				M. Kitazono, T. Sumizawa, Y. Takebayashi, Z.-S. Chen, T. Furukawa, S. Nagayama, A. Tani, S. Takao, T. Aikou, and S.-i. Akiyama Multidrug Resistance and the Lung Resistance-Related Protein in Human Colon Carcinoma SW-620 Cells J Natl Cancer Inst, October 6, 1999; 91(19): 1647 - 1653. [Abstract] [Full Text] [PDF]

				B. D. Stride, S. P. C. Cole, and R. G. Deeley Localization of a Substrate Specificity Domain in the Multidrug Resistance Protein J. Biol. Chem., August 6, 1999; 274(32): 22877 - 22883. [Abstract] [Full Text] [PDF]

				N. Strazielle and J.-F. Ghersi-Egea Demonstration of a Coupled Metabolism-Efflux Process at the Choroid Plexus as a Mechanism of Brain Protection Toward Xenobiotics J. Neurosci., August 1, 1999; 19(15): 6275 - 6289. [Abstract] [Full Text] [PDF]

				M. Kool, M. van der Linden, M. de Haas, G. L. Scheffer, J. M. L. de Vree, A. J. Smith, G. Jansen, G. J. Peters, N. Ponne, R. J. Scheper, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs PNAS, June 8, 1999; 96(12): 6914 - 6919. [Abstract] [Full Text] [PDF]

				T. P. SCHAUB, J. KARTENBECK, J. KÖNIG, H. SPRING, J. DÖRSAM, G. STAEHLER, S. STÖRKEL, W. F. THON, and D. KEPPLER Expression of the MRP2 Gene-Encoded Conjugate Export Pump in Human Kidney Proximal Tubules and in Renal Cell Carcinoma J. Am. Soc. Nephrol., June 1, 1999; 10(6): 1159 - 1169. [Abstract] [Full Text]

				D. R. Hipfner, Q. Mao, W. Qiu, E. M. Leslie, M. Gao, R. G. Deeley, and S. P. C. Cole Monoclonal Antibodies That Inhibit the Transport Function of the 190-kDa Multidrug Resistance Protein, MRP. LOCALIZATION OF THEIR EPITOPES TO THE NUCLEOTIDE-BINDING DOMAINS OF THE PROTEIN J. Biol. Chem., May 28, 1999; 274(22): 15420 - 15426. [Abstract] [Full Text] [PDF]

				T. Hirohashi, H. Suzuki, and Y. Sugiyama Characterization of the Transport Properties of Cloned Rat Multidrug Resistance-associated Protein 3 (MRP3) J. Biol. Chem., May 21, 1999; 274(21): 15181 - 15185. [Abstract] [Full Text] [PDF]

				Y. Cui, J. König, U. Buchholz, H. Spring, I. Leier, and D. Keppler Drug Resistance and ATP-Dependent Conjugate Transport Mediated by the Apical Multidrug Resistance Protein, MRP2, Permanently Expressed in Human and Canine Cells Mol. Pharmacol., May 1, 1999; 55(5): 929 - 937. [Abstract] [Full Text]

				A. TOJO, T. SEKINE, N. NAKAJIMA, M. HOSOYAMADA, Y. KANAI, K. KIMURA, and H. ENDOU Immunohistochemical Localization of Multispecific Renal Organic Anion Transporter 1 in Rat Kidney J. Am. Soc. Nephrol., March 1, 1999; 10(3): 464 - 471. [Abstract] [Full Text]

				M. Kool, M. v. d. Linden, M. de Haas, F. Baas, and P. Borst Expression of Human MRP6, a Homologue of the Multidrug Resistance Protein Gene MRP1, in Tissues and Cancer Cells Cancer Res., January 1, 1999; 59(1): 175 - 182. [Abstract] [Full Text] [PDF]

				J. F. Rebbeor, G. C. Connolly, M. E. Dumont, and N. Ballatori ATP-dependent Transport of Reduced Glutathione on YCF1, the Yeast Orthologue of Mammalian Multidrug Resistance Associated Proteins J. Biol. Chem., December 11, 1998; 273(50): 33449 - 33454. [Abstract] [Full Text] [PDF]

				E. Bakos, R. Evers, G. Szakacs, G. E. Tusnady, E. Welker, K. Szabo, M. de Haas, L. van Deemter, P. Borst, A. Varadi, et al. Functional Multidrug Resistance Protein (MRP1) Lacking the N-terminal Transmembrane Domain J. Biol. Chem., November 27, 1998; 273(48): 32167 - 32175. [Abstract] [Full Text] [PDF]

				M. Alvarez, R. Robey, V. Sandor, K. Nishiyama, Y. Matsumoto, K. Paull, S. Bates, and T. Fojo Using the National Cancer Institute Anticancer Drug Screen to Assess the Effect of MRP Expression on Drug Sensitivity Profiles Mol. Pharmacol., November 1, 1998; 54(5): 802 - 814. [Abstract] [Full Text]

				X.-B. Chang, Y.-X. Hou, and J. R. Riordan Stimulation of ATPase Activity of Purified Multidrug Resistance-associated Protein by Nucleoside Diphosphates J. Biol. Chem., September 11, 1998; 273(37): 23844 - 23848. [Abstract] [Full Text] [PDF]

				J. Wijnholds, G. L. Scheffer, M. van der Valk, P. van der Valk, J. H. Beijnen, R. J. Scheper, and P. Borst Multidrug Resistance Protein 1 Protects the Oropharyngeal Mucosal Layer and the Testicular Tubules against Drug-induced Damage J. Exp. Med., September 7, 1998; 188(5): 797 - 808. [Abstract] [Full Text] [PDF]

				D. S. Miller, R. Masereeuw, J. Henson, and K. J. Karnaky Jr. Excretory transport of xenobiotics by dogfish shark rectal gland tubules Am J Physiol Regulatory Integrative Comp Physiol, September 1, 1998; 275(3): R697 - R705. [Abstract] [Full Text] [PDF]

				C. S. Morrow, P. K. Smitherman, S. K. Diah, E. Schneider, and A. J. Townsend Coordinated Action of Glutathione S-Transferases (GSTs) and Multidrug Resistance Protein 1 (MRP1) in Antineoplastic Drug Detoxification. MECHANISM OF GST A1-1- AND MRP1-ASSOCIATED RESISTANCE TO CHLORAMBUCIL IN MCF7 BREAST CARCINOMA CELLS J. Biol. Chem., August 7, 1998; 273(32): 20114 - 20120. [Abstract] [Full Text] [PDF]

				H. Kusuhara, H. Suzuki, M. Naito, T. Tsuruo, and Y. Sugiyama Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line J. Pharmacol. Exp. Ther., June 1, 1998; 285(3): 1260 - 1265. [Abstract] [Full Text] [PDF]

				M. Gao, M. Yamazaki, D. W. Loe, C. J. Westlake, C. E. Grant, S. P. C. Cole, and R. G. Deeley Multidrug Resistance Protein. IDENTIFICATION OF REGIONS REQUIRED FOR ACTIVE TRANSPORT OF LEUKOTRIENE C4 J. Biol. Chem., April 24, 1998; 273(17): 10733 - 10740. [Abstract] [Full Text] [PDF]

				J.-M. Bréchot, I. Hurbain, A. Fajac, N. Daty, and J.-F. Bernaudin Different Pattern of MRP Localization in Ciliated and Basal Cells from Human Bronchial Epithelium J. Histochem. Cytochem., April 1, 1998; 46(4): 513 - 518. [Abstract] [Full Text]

				Y.-P. Lu, Z.-S. Li, Y. M. Drozdowicz, S. Hortensteiner, E. Martinoia, and P. A. Rea AtMRP2, an Arabidopsis ATP Binding Cassette Transporter Able to Transport Glutathione S-Conjugates and Chlorophyll Catabolites: Functional Comparisons with AtMRP1 PLANT CELL, February 1, 1998; 10(2): 267 - 282. [Abstract] [Full Text] [PDF]

				K. Ito, H. Suzuki, T. Hirohashi, K. Kume, T. Shimizu, and Y. Sugiyama Functional Analysis of a Canalicular Multispecific Organic Anion Transporter Cloned from Rat Liver J. Biol. Chem., January 16, 1998; 273(3): 1684 - 1688. [Abstract] [Full Text] [PDF]

				X.-B. Chang, Y.-X. Hou, and J. R. Riordan ATPase Activity of Purified Multidrug Resistance-associated Protein J. Biol. Chem., December 5, 1997; 272(49): 30962 - 30968. [Abstract] [Full Text] [PDF]

				D. R. Hipfner, K. C. Almquist, E. M. Leslie, J. H. Gerlach, C. E. Grant, R. G. Deeley, and S. P. C. Cole Membrane Topology of the Multidrug Resistance Protein (MRP). A STUDY OF GLYCOSYLATION-SITE MUTANTS REVEALS AN EXTRACYTOSOLIC NH2 TERMINUS J. Biol. Chem., September 19, 1997; 272(38): 23623 - 23630. [Abstract] [Full Text] [PDF]

				B. D. Stride, C. E. Grant, D. W. Loe, D. R. Hipfner, S. P. C. Cole, and R. G. Deeley Pharmacological Characterization of the Murine and Human Orthologs of Multidrug-Resistance Protein in Transfected Human Embryonic Kidney Cells Mol. Pharmacol., September 1, 1997; 52(3): 344 - 353. [Abstract] [Full Text]

				H. E. d. Vries, J. Kuiper, A. G. d. Boer, T. J. C. V. Berkel, and D. D. Breimer The Blood-Brain Barrier in Neuroinflammatory Diseases Pharmacol. Rev., June 1, 1997; 49(2): 143 - 156. [Abstract] [Full Text] [PDF]

				D. W. Loe, R. K. Stewart, T. E. Massey, R. G. Deeley, and S. P. C. Cole ATP-Dependent Transport of Aflatoxin B1 and Its Glutathione Conjugates by the Product of the Multidrug Resistance Protein (MRP) Gene Mol. Pharmacol., June 1, 1997; 51(6): 1034 - 1041. [Abstract] [Full Text]

				H. Ishizuka, K. Konno, H. Naganuma, K. Sasahara, Y. Kawahara, K. Niinuma, H. Suzuki, and Y. Sugiyama Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR) J. Pharmacol. Exp. Ther., March 1, 1997; 280(3): 1304 - 1311. [Abstract] [Full Text]

				M. Gao, D. W. Loe, C. E. Grant, S. P.C. Cole, and R. G. Deeley Reconstitution of ATP-dependent Leukotriene C4 Transport by Co-expression of Both Half-molecules of Human Multidrug Resistance Protein in Insect Cells J. Biol. Chem., November 1, 1996; 271(44): 27782 - 27787. [Abstract] [Full Text] [PDF]