Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediates Resistance to Mitoxantrone via Glutathione-Dependent Drug Efflux

Morrow, Charles S.; Peklak-Scott, Christina; Bishwokarma, Bimjhana; Kute, Timothy E.; Smitherman, Pamela K.; Townsend, Alan J.

doi:10.1124/mol.105.017988

Cited by 91 publications

(66 citation statements)

References 25 publications

(32 reference statements)

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“…Using an estimated cell volume of 1.4 pL (May and Qu, 2005), the intracellular DEPMPO/ • SG is estimated at 10.7-16 µM. This is well below the typical mM levels of total GSH in cells (Meister and Anderson, 1983;Morrow et al, 2006). The relatively low levels of GS • spin adducts are therefore consistent with the essentially normal levels and redox status of GSH in Cr(VI)-exposed cells (Fig.…”

Section: Discussionmentioning

confidence: 56%

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

2008

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Hexavalent chromium [Cr(VI)] species such as chromates are cytotoxic. Inhalational exposure is a primary concern in many Cr-related industries and their immediate environments, and bronchial epithelial cells are directly exposed to inhaled Cr(VI). Chromates are readily taken up by cells and are reduced to reactive Cr species which may also result in the generation of reactive oxygen species (ROS). The thioredoxin (Trx) system has a key role in the maintenance of cellular thiol redox balance and is essential for cell survival. Cells normally maintain the cytosolic (Trx1) and mitochondrial (Trx2) thioredoxins largely in the reduced state. Redox western blots were used to assess the redox status of the thioredoxins in normal human bronchial epithelial cells (BEAS-2B) incubated with soluble Na 2 CrO 4 or insoluble ZnCrO 4 for different periods of time. Both chromates caused a doseand time-dependent oxidation of Trx2 and Trx1. Trx2 was more susceptible in that it could all be converted to the oxidized form, whereas a small amount of reduced Trx1 remained even after prolonged treatment with higher Cr concentrations. Only one of the dithiols, presumably the active site, of Trx1 was oxidized by Cr(VI). Cr(VI) did not cause significant GSH depletion or oxidation indicating that Trx oxidation does not result from a general oxidation of cellular thiols. With purified Trx and thioredoxin reductase (TrxR) in vitro, Cr(VI) also resulted in Trx oxidation. It was determined that purified TrxR has pronounced Cr(VI) reducing activity, so competition for electron flow from TrxR might impair its ability to reduce Trx. The in vitro data also suggested some direct redox interaction between Cr(VI) and Trx. The ability of Cr(VI) to cause Trx oxidation in cells could contribute to its cytotoxic effects, and could have important implications for cell survival, redoxsensitive cell signaling, and the cells' tolerance of other oxidant insults.

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Section: Discussionmentioning

confidence: 56%

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

2008

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“…1B). A similar cotransport or cross-stimulated transport mechanism has also been proposed recently for GSH and the anthracene antineoplastic agent mitoxantrone (Morrow et al, 2006). Substrates such as estrone sulfate and NNAL-O-glucuronide (4-(nitrosamino)-1-(3-pyridyl)-1-butanol-O-glucuronide) are also transported at markedly increased levels when GSH is present (Leslie et al, 2001a;Qian et al, 2001).…”

mentioning

confidence: 91%

Mechanistic Differences between GSH Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) and GSH Modulation of MRP1-Mediated Transport

Rothnie¹,

Conseil²,

Lau³

et al. 2008

Mol Pharmacol

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Multidrug resistance protein 1 (MRP1/ABCC1) is an ATPdependent polytopic membrane protein that transports many anticancer drugs and organic anions. Its transport mechanism is multifaceted, especially with respect to the participation of GSH. For example, vincristine is cotransported with GSH, estrone sulfate transport is stimulated by GSH, or MRP1 can transport GSH alone, and this can be stimulated by compounds such as verapamil or apigenin. Thus, the interactions between GSH and MRP1 are mechanistically complex. To examine the similarities and differences among the various GSH-associated mechanisms of MRP1 transport, we have measured first the effect of GSH and several GSHassociated substrates/modulators on the binding and hydrolysis of ATP by MRP1 using 8-azidoadenosine-5Ј-[32 P]-triphosphate ([ 32 P]azidoATP) analogs, and second the initial binding of GSH and GSH-associated substrates/modulators to MRP1. We observed that GSH or its nonreducing derivative S-methylGSH (S-mGSH), but none of the GSH-associated substrate/modulators, caused a significant increase in [␥-32 P]azidoATP labeling of MRP1. Moreover, GSH and S-mGSH decreased levels of orthovanadate-induced trapping of [␣-32 P]azidoADP. [␣-32 P]azidoADP.Vi trapping was also decreased by estone sulfate, whereas vincristine, verapamil, and apigenin had no apparent effects on nucleotide interactions with MRP1. Furthermore, estrone sulfate and S-mGSH enhanced the effect of each other 15-and 10-fold, respectively. Second, although GSH binding increased the apparent affinity of MRP1 for all GSH-associated substrates/ modulators tested, only estrone sulfate had a reciprocal effect on the apparent affinity of MRP1 for GSH. Overall, these results indicate significant mechanistic differences between MRP1-mediated transport of GSH and the ability of GSH to modulate MRP1 transport.

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“…p-Aminohippuric acid [92] 372 Bilirubin biglucuronide [93] 0.8 a Daunorubicin [94,95] 1.4 Atazanavir [59] Bilirubin bisglucuronide [93] Bilirubin monoglucuronide [93] 0.4 a Grepafloxacin [96] Benzbromarone [97,98] Bilirubin monoglucuronide [93] E217bG [99] 22 Irinotecan [100] Benzylpenicillin [98] DHEAS [101] 5 Estradiol sulfate [102] 0.4 Methotrexate [98,103,104] 930/2150 Daunorubicin [99]~8a DNP-GS [105] 3.6 E23SO417bG [99] 1.7 Doxorubicin [99]~5 0 a E217bG [99,[105][106][107] 1.5-4.8 E316bG [99] 45 Mitoxantrone [108] Flurbiprofen [109] Estrone-3-sulfate [102] 0.7/4.2 E317bG [99] 1.4 Saquinavir [110] Furosemide [98] Folic acid [103] Estrone-3-sulfate [102] 0.5 Vinblastine [111] Glibenclamide [77] Glutathione [97,112] Glycholate [99] Vincristine [95,113] Indinavir [114] Leucovorin [103] Glycolithocholate-3-sulfate [99] 1.4 Indometacin …”

Section: Substrates and Inhibitorsmentioning

confidence: 99%

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

Grandvuinet

Vestergaard

Rapin³

et al. 2012

Journal of Pharmacy and Pharmacology

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Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in‐vitro methods presently employed in drug–drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium‐dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3‐5, the multidrug resistance associated proteins (MRP) 1–6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter α/β (OSTα/β) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in‐vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in‐vitro parameters for transporters (Km/Ki/IC50, efflux ratio). The applicability of using a cut‐off value (estimated based on the intestinal drug concentration divided by the Ki or IC50) has also been considered. Summary A re‐evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P‐glycoprotein. Moreover, the interplay between various processes that a drug is subject to in‐vivo such as translocation by several transporters and dissolution should be considered.

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Multidrug Resistance Protein 1 (MRP1, ABCC1) Mediates Resistance to Mitoxantrone via Glutathione-Dependent Drug Efflux

Cited by 91 publications

References 25 publications

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

Hexavalent chromium causes the oxidation of thioredoxin in human bronchial epithelial cells

Mechanistic Differences between GSH Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) and GSH Modulation of MRP1-Mediated Transport

Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug–drug interactions

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