Bioflavonoid Stimulation of Glutathione Transport by the 190-kDa Multidrug Resistance Protein 1 (MRP1)

Leslie, Elaine M.; Deeley, Roger G.; Cole, Susan P.C.

doi:10.1124/dmd.31.1.11

Cited by 114 publications

(96 citation statements)

References 25 publications

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“…Reduced glutathione was proven to be a poor substrate of MRP1 [79,87], but its transport is stimulated by bioflavonoids and verapamil by increasing the apparent affinity of the transporter for GSH [82,88]. In contrast, GSSG by itself was found to be a substrate with an apparent K m value of around 100 μM [79].…”

Section: Dual Role Of Mrp1 In the Physiological Barriersmentioning

confidence: 99%

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Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

Bakos

Homolya

2006

Pflugers Arch - Eur J Physiol

153

104

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MRP1 (ABCC1) is a peculiar member of the ABC transporter superfamily for several aspects. This protein has an unusually broad substrate specificity and is capable of transporting not only a wide variety of neutral hydrophobic compounds, like the MDR1/P-glycoprotein, but also facilitating the extrusion of numerous glutathione, glucuronate, and sulfate conjugates. The transport mechanism of MRP1 is also complex; a composite substratebinding site permits both cooperativity and competition between various substrates. This versatility and the ubiquitous tissue distribution make this transporter suitable for contributing to various physiological functions, including defense against xenobiotics and endogenous toxic metabolites, leukotriene-mediated inflammatory responses, as well as protection from the toxic effect of oxidative stress. In this paper, we give an overview of the considerable amount of knowledge which has accumulated since the discovery of MRP1 in 1992. We place special emphasis on the structural features essential for function, our recent understanding of the transport mechanism, and the numerous assignments of this transporter.

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Section: Dual Role Of Mrp1 In the Physiological Barriersmentioning

confidence: 99%

“…These are exemplified by estrone 3-sulfate, 4-(methylnitrosami- [84,127,133]. In contrast to these substrates, certain compounds, such as verapamil and bioflavonoids, are not transported by MRP1 but they enhance the MRP1-mediated transport of GSH [82,88].…”

Section: Handling Of Substratesmentioning

confidence: 99%

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

Bakos

Homolya

2006

Pflugers Arch - Eur J Physiol

153

104

View full text Add to dashboard Cite

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“…Furthermore, it has been demonstrated that the binding of two MRP1-specific modulating agents, agosterol A and LY475776, is dependent on GSH (Ren et al, 2001;Mao et al, 2002). Interestingly, xenobiotics such as verapamil and several dietary flavonoids (including the flavone apigenin), stimulate GSH transport by MRP1 up to 4-fold without being transported themselves (Loe et al, 2000;Leslie et al, 2001cLeslie et al, , 2003. Overall, the interaction between MRP1 and GSH is complex and presently is not well understood.…”

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confidence: 99%

Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)

Leslie

Bowers²,

Deeley³

et al. 2003

J Pharmacol Exp Ther

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The human multidrug resistance protein 1 (MRP1) is a primary active transporter of reduced (GSH) and oxidized glutathione, as well as GSH-, glucuronate-, and sulfate-conjugated organic anions. In addition, the transport of certain MRP1 substrates is stimulated by the presence of GSH. To evaluate the structural features of GSH required for interaction with the protein, we investigated the ability of a series of GSH analogs to enhance GSH stimulatable transport of [ 3 H]estrone 3-sulfate (E 1 SO 4 ). We found that substitution of the ␥-Glu residue with Gly, ␤-Asp, and ␣-Glu resulted in complete loss of transport stimulation. In contrast, substitution of Gly with Glu or ␤-Ala resulted in only a partial loss of stimulatory activity. E 1 SO 4 transport activity surpassed GSH-stimulated levels in the presence of tripeptides in which Cys was substituted with the hydrophobic amino acids Leu, Phe, and homo-Phe. Moreover, polar substitutions of Cys did not enhance transport to the same extent as nonpolar substitutions of comparable size. ␥-Glu-Leu-Gly was 1.6-fold more effective than GSH in stimulating E 1 SO 4 uptake, and kinetic analysis indicated this was due to an increased V max . In addition, this tripeptide was shown to be a competitive inhibitor of apigenin-stimulated GSH transport (K i value of 14 M), confirming that it either interacts with the same site on MRP1 as GSH or that the binding of the two tripeptides is mutually exclusive. These data provide insight into the architecture of the GSH binding domain of MRP1.

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“…It was later found that some flavonoids have the same effect on MRP1 [40]. Hydroxychalcones, the precursors of flavonoids, were also found to induce GSH depletion, although the MRP(s) involved remain to be identified [41].…”

Section: Mrps and Glutathionementioning

confidence: 99%

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

Leitner

Kachadourian

Day

2007

Biochemical Pharmacology

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The ATP-binding cassette (ABC) class of proteins is one of the most functionally diverse transporter families found in biological systems. Although the abundance of ABC proteins varies between species, they are highly conserved in sequence and often demonstrate similar functions across prokaryotic and eukaryotic organisms. Beginning with a brief summary of the events leading to our present day knowledge of ABC transporters, the purpose of this review is to discuss the potential for utilizing ABC transporters as a means for cellular glutathione (GSH) modulation. GSH is one of the most abundant thiol antioxidants in cells. It is involved in cellular division, protein and DNA synthesis, maintenance of cellular redox status and xenobiotic metabolism. Cellular GSH levels are often altered in many disease states including cancer. Over the past two decades there has been considerable emphasis on methods to sensitize cancer cells to chemotherapeutics and ionization radiation therapy by GSH depletion. We contend that ABC transporters, particularly multi-drug resistant proteins (MRPs), may be used as therapeutic targets for applications aimed at modulation of GSH levels. This review will emphasize MRP-mediated modulation of intracellular GSH levels as a potential alternative and adjunctive approach for cancer therapy.

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Bioflavonoid Stimulation of Glutathione Transport by the 190-kDa Multidrug Resistance Protein 1 (MRP1)

Cited by 114 publications

References 25 publications

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

Portrait of multifaceted transporter, the multidrug resistance-associated protein 1 (MRP1/ABCC1)

Structural Requirements for Functional Interaction of Glutathione Tripeptide Analogs with the Human Multidrug Resistance Protein 1 (MRP1)

Harnessing drug resistance: Using ABC transporter proteins to target cancer cells

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