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Substrate Recognition and Transport by Multidrug Resistance Protein 1 (ABCC1)

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Substrate Recognition and Transport by Multidrug Resistance Protein 1 (ABCC1) View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector FEBS Letters 580 (2006) 1103–1111 Minireview Substrate recognition and transport by multidrug resistance protein 1 (ABCC1) Roger G. Deeley*, Susan P.C. Cole Division of Cancer Biology and Genetics, Cancer Research Institute, Queen’s University, Kingston, Ont., Canada K7L 3N6 Received 7 November 2005; revised 9 December 2005; accepted 13 December 2005 Available online 21 December 2005 Edited by Gerrit van Meer glutathione (GSH) synthesis inhibitor, buthionine sulfoximine Abstract Multidrug resistance protein (MRP) 1 belongs to the ‘C’ branch of the ABC transporter superfamily. MRP1 is a high- (BSO) as a consequence of an unexplained 6-fold decrease in cellular GSH levels relative to parental H69 cells [5]. The affinity transporter of the cysteinyl leukotriene C4 and is respon- sible for the systemic release of this cytokine in response to an cross-resistance of H69AR cells to natural products such as inflammatory stimulus. However, the substrate specificity of Vinca alkaloids and epipodophyllotoxins, as well as anthracy- MRP1 is extremely broad and includes many organic anion con- clines, suggested the possible involvement of P-glycoprotein jugates of structurally unrelated endo- and xenobiotics. In addi- (P-gp/ABCB1), which at the time was the only known human tion, MRP1 transports unmodified hydrophobic compounds, such multidrug transporter [6]. However, resistance was not modu- as natural product type chemotherapeutic agents and mutagens, lated by agents that reversed P-gp-mediated resistance, and no such as aflatoxin B1. Transport of several of these compounds increase in P-gp levels could be detected [2,7,8]. In contrast, the has been shown to be dependent on the presence of reduced glu- MRP1 gene was extensively amplified in H69AR cells and tathione (GSH). More recently, GSH has also been shown to stimulate the transport of some conjugated compounds, including MRP1 mRNA levels were elevated approximately 100-fold sulfates and glucuronides. Here, we summarize current knowl- [1]. The marked increase in levels of MRP1 mRNA relative edge of the substrate specificity and modes of transport of to the parental H69 cells facilitated the cloning of MRP1 MRP1 and discuss how the protein may recognize its structur- cDNA by differential hybridization. Sequencing of MRP1 re- ally diverse substrates. vealed it to be an ABC transporter, but only very distantly re- Ó 2005 Federation of European Biochemical Societies. Published lated to P-gp. Its closest known human relative at the time was by Elsevier B.V. All rights reserved. the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7). Despite the lack of amino acid sequence Keywords: Multidrug resistance protein 1; Leukotriene C4; identity with P-gp (approximately 19% overall), gene transfec- Glutathione; Atomic homology model; Site-directed tion experiments confirmed the ability of MRP1 to confer mutagenesis; Organic anion transport; ABC transporter; Multidrug resistance resistance to a number of natural product drugs, as well as arsenical and antimonial oxyanions, consistent with the estab- lished phenotype of H69AR cells [9,10]. It is now known that MRP1 is a member of a family of nine, possibly ten, proteins in humans, the members of which have been characterized functionally to varying extents, as described elsewhere in this 1. Introduction issue. The MRPs (ABCC1–6, 10–12), together with the ATP- gated chloride channel, CFTR (ABCC7), and the ATP-depen- Multidrug resistance protein 1 (MRP1/ABCC1) was identi- dent sulfonylurea receptors (SURs) (ABCC8 and ABCC9), fied in 1992 as the cause of multidrug resistance in an anthra- which are potassium channel regulators, comprise the ‘C’ cycline selected human small cell lung carcinoma cell line, branch of the ABC superfamily [11]. H69AR [1]. The drug resistance profile of H69AR cells in- Clinical studies have documented the expression of MRP1 in cludes several classes of natural product cytotoxic agents, as a range of solid and haematological cancers and, in some well as certain heavy metal oxyanions [2–4]. An intriguing fea- cases, have correlated MRP1 expression with negative re- ture of the H69AR cells was their collateral sensitivity to the sponse to treatment and disease outcome. These studies have been reviewed extensively elsewhere [12–15]. In this minire- *Corresponding author. Fax: +1 613 533 6830. view, we summarize current knowledge of the substrate speci- E-mail address: [email protected] (R.G. Deeley). ficity and modes of transport of MRP1 and discuss how the protein may recognize its diverse substrates (see Table 1). Abbreviations: BSO, buthionine sulfoximine; LTC4, leukotriene C4; MRP1, multidrug resistance protein 1; P-gp, P-glycoprotein; CFTR, cystic fibrosis transmembrane conductance regulator; E217bG, estra- diol-17b-D-glucuronide; GSH, glutathione; NBD, nucleotide-binding 2. Substrate specificity of MRP1 domain; MSD, membrane spanning domain; SUR, sulfonylurea rec- eptor; MALDI TOF, matrix-assisted laser desorption/ionization time The convergence of several unrelated lines of investigation of flight; NNAL, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol; TM, contributed to the early identification of a large number of transmembrane 0014-5793/$32.00 Ó 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.febslet.2005.12.036 1104 R.G. Deeley, S.P.C. Cole / FEBS Letters 580 (2006) 1103–1111 Table 1 with functional characteristics similar to that of the hepato- Substances transported by MRP1 (ABCC1) canalicular transporter defective in the TRÀ and Esai rats Compound Class Examples [19]. In fact, the transport defect in these rats and in Dubin– Drugs/Xenobiotics Johnson Syndrome involves MRP2 (ABCC2) whereas the Antineoplastics Folate-based antimetabolites transporter in mast cells and eosinophils is MRP1. Neverthe- (methotrexate, edatrexate, ZD1694), less, because the substrate specificities of the two proteins over- anthracyclines (doxorubicin, lap extensively, the information from both lines of daunorubicin, epirubicin, idarubicin), plant alkaloids (etoposide, vincristine, investigation was extremely useful in the early characterization vinblastine, paclitaxel, irinotecan, SN-38), of the substrate profiles of MRP1 and subsequently, MRP2. antiandrogens (flutamide, The first MRP1 substrate identified by vesicle transport hydroxyflutamide) studies was the conjugated cysteinyl leukotriene C4 (LTC4), Antivirals Saquinavir, ritonavir which was a known substrate of the conjugated organic anion Antibiotics Difloxacin, grepafloxacin Metalloids Sodium arsenite, sodium arsenate, transporter in mast cells [20–23] (Fig. 1). Mouse knock-out potassium antimonite, potassium studies have confirmed that this inflammatory cytokine is in- antimony tartrate deed a physiological substrate of MRP1 [24]. The protein Fluorescent probes Calcein, Fluo-3, BCECF, SNARF has also been shown to be capable of ATP-dependent trans- Toxicants Aflatoxin B1, methoxychlor, fenitrothion, chlorpropham port of anionic glutathione, glucuronide and sulfate conjugates of an extremely diverse array of endo- and xenobiotics (re- Drug/Xenobiotic conjugates viewed in [13,25,26]). The structural diversity of some exam- GSH conjugates 2,4-Dinitrophenyl-SG, bimane-SG, ples of the better characterized MRP1 substrates is N-ethylmaleimide-SG, doxorubicin-SG, illustrated in Fig. 1. The affinity of MRP1 for some of its sub- thiotepa-SG, cyclophosphamide-SG, melphalan-SG, chlorambucil-SG, strates is relatively high for such a promiscuous transporter. ethacrynic acid-SG, metolachlor-SG, For example, the Km values for LTC4 and the GS-conjugate atrazine-SG, sulforaphane-SG, aflatoxin of aflatoxin B1 epoxide are 100–200 nM [22,27]. The protein B1-epoxide-SG, 4-nitroquinoline can also display surprising structural specificity. For example, 1-oxide-SG, As(SG)3 Glucuronide conjugates Etoposide-Gluc, 4-(methylnitrosamino)- 17b and 16a glucuronides of estriol differ by more than 20-fold 1-(3-pyridyl)-1-butanol (NNAL)-3b-O- in their ability to competitively inhibit LTC4 transport [28]. Gluc, SN-38-gluc, 4-methylumbelliferyl- One of the general observations to emerge from vesicular b-D-gluc, 6-hydroxy-5,7-dimethyl-2- transport studies of MRP1 is that structurally unrelated com- methylamino-4-(3-pyridylmethyl) pounds with different anionic substituents, which may be sub- benzothiazole sulfate (E3040S)-Gluc strates or simply able to bind to the protein without being Naturally occurring metabolites transported, often act as competitive inhibitors of transport GSH conjugates Leukotriene C4, prostaglandin A2-SG, of well-characterized substrates such as LTC4 and estradiol- 15-deoxy-D12,14 prostaglandin J -SG, 2 17b-D-glucuronide (E217bG) [22,28]. The studies also show hydroxynonenal-SG that the rank order of potency of inhibition is substrate depen- Glucuronide conjugates 17b-Estradiol-17-b-D-gluc, glucuronosylbilirubin, bis- dent, prompting the suggestion that the substrates and ‘inhib- lucuronosylbilirubin, hyodeoxycholate-6- itors’ establish distinct but overlapping sets of contacts with a a-Gluc common binding pocket on the protein [22,29]. Sulfate conjugates Estrone 3-sulfate, dehydroepiandrosterone sulfate, sulfatolithocholate Folates Folic acid, L-leucovorin 3. Modes of MRP1-mediated transport Peptides GSH, GSSG Other Bilirubin Although gene transfer experiments confirmed that MRP1 could enhance the efflux of several natural
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