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Multidrug-Resistance Protein 5 Is a Multispecific Organic Anion Transporter Able to Transport Nucleotide Analogs Jan Wijnholds*, Carla A

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Multidrug-Resistance Protein 5 Is a Multispecific Organic Anion Transporter Able to Transport Nucleotide Analogs Jan Wijnholds*, Carla A Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs Jan Wijnholds*, Carla A. A. M. Mol*, Liesbeth van Deemter*, Marcel de Haas*, George L. Scheffer†, Frank Baas‡, Jos H. Beijnen§, Rik J. Scheper†, Sigrid Hatse¶, Erik De Clercq¶, Jan Balzarini¶, and Piet Borst*ʈ *Division of Molecular Biology and Center for Biomedical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands; †Department of Pathology, University Hospital Free University, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands; ‡Department of Neurology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands; §Department of Pharmacy, Slotervaart Hospital, Louwesweg 6, 1066 EC Amsterdam, The Netherlands; and ¶Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium Contributed by Piet Borst, April 10, 2000 Two prominent members of the ATP-binding cassette superfamily nylmethoxyethyl)adenine (PMEA) (23). No resistance against of transmembrane proteins, multidrug resistance 1 (MDR1) P- (anticancer or antiviral) drugs has been reported for MRP5 or glycoprotein and multidrug resistance protein 1 (MRP1), can me- MRP6. diate the cellular extrusion of xenobiotics and (anticancer) drugs We generated cell lines overexpressing human MRP5 and from normal and tumor cells. The MRP subfamily consists of at least studied the (anticancer͞antiviral) drug resistance spectrum, the six members, and here we report the functional characterization of transport characteristics, and the intracellular localization of human MRP5. We found resistance against the thiopurine antican- MRP5 in polarized epithelial cells (24). We find that MRP5 is an cer drugs, 6-mercaptopurine (6-MP) and thioguanine, and the organic anion transporter with the remarkable ability to confer anti-HIV drug 9-(2-phosphonylmethoxyethyl)adenine (PMEA) in resistance to base and nucleotide analogs. MRP5-transfected cells. This resistance is due to an increased extrusion of PMEA and 6-thioinosine monophosphate from the Materials and Methods cells that overproduce MRP5. In polarized Madin–Darby canine Materials. 6-Mercaptopurine (6-MP) 14C-labeled at position 8 kidney II (MDCKII) cells transfected with an MRP5 cDNA construct, and bis(pivaloyloxymethyl)-PMEA (bis-POM-PMEA) 3H- MRP5 is routed to the basolateral membrane and these cells labeled at position 8 were obtained from Moravek Biochemicals transport S-(2,4-dinitrophenyl)glutathione and glutathione prefer- (Brea, CA). 1-Chloro-2,4-dinitro[14C]benzene ([14C]CDNB) was entially toward the basal compartment. Inhibitors of organic anion from Amersham. PMEA was kindly provided by M. Bijsterbosch transport inhibit transport mediated by MRP5. We speculate that (Leiden͞Amsterdam Center for drug research, Leiden, The MRP5 might play a role in some cases of unexplained resistance to Netherlands), and PMEA and bis-POM-PMEA were from N. thiopurines in acute lymphoblastic leukemia and/or to antiretro- Bischofberger (Gilead Sciences, Foster City, CA). viral nucleoside analogs in HIV-infected patients. Cell Lines. 293 Human Embryonic Kidney (HEK) cells (25) and ancer cells that overproduce drug-transporting proteins may Madin–Darby canine kidney II (MDCKII) cells (26) were grown Cbecome resistant to a wide spectrum of drugs with different in DMEM (GIBCO͞BRL) containing 10% FCS and penicillin͞ structures or cellular targets, a phenomenon called multidrug streptomycin. resistance (MDR) (1). ATP-dependent transmembrane drug transporters such as the MDR1 P-glycoprotein (P-gp, ABCB1) Cloning and Sequencing of MRP5 cDNA. Two PCR primers [base (1) and the multidrug-resistance protein (MRP1, ABCC1) (2) pairs 18–37 and 345–326 from expressed sequence tag (EST) can render cells multidrug resistant in vitro, and it is likely that H69466 containing the first ATP-binding domain of a MRP these proteins contribute to the (intrinsic or acquired) resistance family member] were used to generate a 327-bp cDNA probe against anticancer drugs used in patients. from a human fetal brain ␭ DR2 cDNA library (CLONTECH). MRP1 is a glutathione (GSH) conjugate (GS-X) pump or This probe was used to screen a 5Ј-stretch human fetal brain multispecific organic anion transporter (MOAT) (3). MRP1 can ␭gt11 cDNA library (CLONTECH). We obtained several long mediate the transport of negatively charged conjugated hydro- cDNA clones containing the first and second ATP-binding philic compounds with a large hydrophobic moiety such as domains as well as the complete 3Ј untranslated region. How- glutathione S-, glucuronide, and sulfate conjugates of drugs (3–6). It can extrude neutral and basic organic compounds if the cell contains normal levels of GSH (7–10), probably by cotrans- Abbreviations: GSH, glutathione; GS-X, GSH conjugate; DNP-GS, S-(2,4-dinitrophenyl)glu- port of the drug with GSH (7, 8). Whereas the function of tathione; CDNB, 1-chloro-2,4-dinitrobenzene; CMV, cytomegalovirus; HEK, human embry- onic kidney cells; 5-HP, 5-hydroxypyridine-2-carboxaldehyde thiosemicarbazone; MDCKII P-glycoprotein in normal tissues appears to be limited to defense cells, Madin–Darby canine kidney II cells; MDR, multidrug resistance; 6-MP, 6-mercaptopu- against drugs and other xenotoxins, MRP1 not only is involved rine; MTX, methotrexate; MRP1, MDR protein 1; PMEA, 9-(2-phosphonylmethoxyethyl)ad- in reducing the passage of drugs across some specialized epi- enine; bis-POM-PMEA, bis(pivaloyloxymethyl)-PMEA; PMEAp, PMEA monophosphate; thelia (11, 12) but also is the major transporter for endogenous PMEApp, PMEA diphosphate; tIMP, 6-thioinosine monophosphate. leukotriene C4 (LTC4), an important mediator of the inflam- Data deposition: The sequence reported in this paper has been deposited in the GenBank matory response (13, 14). database (accession no. U83661). Several other MRP family members (MRP2–6, ABCC2–6) ʈTo whom reprint requests should be addressed at: Division of Molecular Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. may play a role in MDR (15–17): MRP2 has been shown to E-mail: [email protected]. confer low-level resistance to the anticancer drugs cisplatin, The publication costs of this article were defrayed in part by page charge payment. This etoposide, vincristine, and methotrexate (MTX) (18–20), MRP3 article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. to etoposide, vincristine, and MTX (15, 21, 22), and MRP4 to §1734 solely to indicate this fact. acyclic nucleoside phosphonates [e.g., 9-(2-phosphonylmethoxy- Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073͞pnas.120159197. ethyl)guanine (PMEG)] and the anti-HIV drug 9-(2-phospho- Article and publication date are at www.pnas.org͞cgi͞doi͞10.1073͞pnas.120159197 7476–7481 ͉ PNAS ͉ June 20, 2000 ͉ vol. 97 ͉ no. 13 Downloaded by guest on September 25, 2021 ever, about 1 kb of 5Ј coding and noncoding sequences was not described previously (32). Briefly, cells were washed in HBSS retrieved from this library. Using total RNA from the human and incubated at room temperature with 2 ␮M[14C]CDNB in ovarian carcinoma cell line 2008A and a 5Ј-RACE protocol HBSS applied to both the apical and basal compartments. (GIBCO͞BRL), we isolated the missing 5Ј end. MRP5 cDNA Samples of medium from each compartment were taken at was sequenced with the Applied Biosystems ABI377 automatic several time points. The water-soluble [14C]DNP-GS was sepa- sequencer. The GenBank accession number is U83661 (16). rated from the hydrophobic [14C]CDNB by extraction of the samples with ethyl acetate, and radioactivities of samples were Overproduction of MRP5 in 293 HEK and MDCKII Cells. The MRP5 quantitated in a liquid scintillation counter. cDNA was assembled in pGEM5Zf to generate pGEM5Zf- MRP5. We modified the retroviral expression vector pBABE- Accumulation and Efflux Assays. For accumulation studies (n ϭ 6), puro (27), by insertion of a blunted 500-bp HindIII–HindIII 293 and 293͞MRP5 cells were plated in triplicate at a density of fragment containing the cytomegalovirus (CMV) promoter 5 ϫ 105 cells per well of a poly(L-lysine)-treated 12-well plate from pCMV-neo-cjun (28) into the blunted BamHI site of overnight. Cells were incubated with 0.5 ml of 0.4, 2.0, or 10 ␮M pBABE-puro, resulting in pBABE-CMV-puro. A blunted [8-14C]-6-MP (54 Ci͞mol; 1 Ci ϭ 37 GBq) for 30 min at 37°C in EcoRI–HindIII fragment containing the complete MRP5 cDNA prewarmed DMEM͞10% FCS medium, equilibrated under 5% ͞ was subcloned behind the CMV promoter in the blunted BamHI CO2, and containing penicillin streptomycin. After drug accu- site of the retroviral vector pBABE-CMV-puro to generate mulation, medium was removed, and cells were put on ice, pBABE-CMV-MRP5-puro. By using a calcium phosphate pre- washed three times with 2 ml of ice-cold PBS, treated in 0.2 ml cipitation cell transfection kit (GIBCO͞BRL), the retroviral of trypsin solution, and added to 4 ml of scintillation mix to vector was transfected into the packaging cell line Phoenix (29), measure radioactivity. and supernatants containing retrovirus particles were used to For efflux studies, 293 and 293͞MRP5 cells were plated in transduce 293 and MDCKII cells. MRP5-overproducing cells triplicate at a density of 2 ϫ 106 cells per well of a poly(L-lysine)- were identified on immunoblots using monoclonal antibodies treated 12-well plate overnight. Drug loading under ATP- (mAbs) directed against human MRP5 (M5I-1 or M5II-54). depleting conditions was performed for2hinglucose-free, pyruvate-free DMEM (GIBCO͞BRL) containing 5% dialyzed mAbs. For the generation of mAbs against MRP5, we subcloned FCS, 10 mM deoxyglucose, 10 mM sodium azide, and 10 ␮M the MRP5 cDNA coding for amino acids 722–910, or for amino [8-14C]-6-MP (54 Ci͞mol) or 1 ␮M bis-POM-[3H]PMEA (3 acids 82–168, into the pmal-c vector (New England Biolabs) for Ci͞mmol). After loading, the wells were washed quickly with production of a fusion protein of Escherichia coli maltose- PBS, and incubated with prewarmed complete medium at 37°C.
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