Modulation of Multidrug Resistance Protein 1 (MRP1/ABCC1) Transport and ATPase Activities by Interaction with Dietary Flavonoids

Leslie, Elaine M.; Mao, Qingcheng; Oleschuk, Curtis J.; Deeley, Roger G.; Cole, Susan P. C.

doi:10.1124/mol.59.5.1171

Cited by 216 publications

(204 citation statements)

References 40 publications

Supporting

Mentioning

183

Contrasting

Order By: Relevance

“…Human MRP3 plasmid (pcNDA3.1(2)-MRP3) and MRP4 plasmid (pcDNA3.1(2)-MRP4) were kindly provided by Dr. Susan Cole (Queen's University, Kingston, ON, Canada) and Dr. Dietrich Keppler (German Cancer Research Center, Heidelberg, Germany), respectively. Transiently transfected human embryonic kidney cells (HEK293T) were generated and membrane vesicles were prepared as described previously (Leslie et al, 2001). Transport experiments were carried out by a rapid filtration assay as described previously (Ghibellini et al, 2008).…”

Section: Methodsmentioning

confidence: 99%

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Pfeifer

Yang

Brouwer

2013

J Pharmacol Exp Ther

103

View full text Add to dashboard Cite

Transporters responsible for hepatic uptake and biliary clearance (CL Bile ) of rosuvastatin (RSV) have been well characterized. However, the contribution of basolateral efflux clearance (CL BL ) to hepatic and systemic exposure of RSV is unknown. Additionally, the appropriate design of in vitro hepatocyte efflux experiments to estimate CL Bile versus CL BL remains to be established. A novel uptake and efflux protocol was developed in sandwich-cultured hepatocytes (SCH) to achieve desired tight junction modulation while maintaining cell viability. Subsequently, studies were conducted to determine the role of CL BL in the hepatic disposition of RSV using SCH from wild-type (WT) and multidrug resistance-associated protein 2 (Mrp2)-deficient (TR 2 ) rats in the absence and presence of the P-glycoprotein and breast cancer resistance protein (Bcrp) inhibitor elacridar (GF120918). RSV CL Bile was nearly ablated by GF120918 in TR 2 SCH, confirming that Mrp2 and Bcrp are responsible for the majority of RSV CL Bile . Pharmacokinetic modeling revealed that CL BL and CL Bile represent alternative elimination routes with quantitatively similar contributions to the overall hepatocellular excretion of RSV in rat SCH under baseline conditions (WT SCH in the absence of GF120918) and also in human SCH. Membrane vesicle experiments revealed that RSV is a substrate of MRP4 (K m 5 21 6 7 mM, V max 5 1140 6 210 pmol/min per milligram of protein). Alterations in MRP4-mediated RSV CL BL due to drug-drug interactions, genetic polymorphisms, or disease states may lead to changes in hepatic and systemic exposure of RSV, with implications for the safety and efficacy of this commonly used medication.

show abstract

Section: Methodsmentioning

confidence: 99%

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Pfeifer

Yang

Brouwer

2013

J Pharmacol Exp Ther

103

View full text Add to dashboard Cite

show abstract

“…-enriched membrane vesicle proteins were photolabeled with 8-azido-[␣-32 P]ATP essentially as described (46,47). Briefly, membrane vesicles (20 g) were dispersed in 20 l of transport buffer containing 5 mM MgCl 2 and 5 M 8-azido-[␣-32 P]ATP (1 Ci).…”

Section: Photolabeling Of Mrp1 By 8-azido-[␣-32 P]atp-mrp1mentioning

confidence: 99%

“…GSH transport was measured in the presence of apigenin (30 M), which previous studies have shown markedly enhances the uptake of this tripeptide by MRP1, thereby allowing more accurate quantitation (13,47). Relative to wild-type MRP1, GSH uptake by six of the nine MSD2 Pro mutants (P323A, P343A, P448A, P478A, P557A, and P595A) was substantially reduced (60 -93%), whereas GSH uptake levels by the P359A, P464A, and P600A mutants were comparable with wild-type MRP1 (Table II).…”

Section: Expression Levels and Transport Activities Of Mrp1 Mutants Cmentioning

confidence: 99%

Identification of Proline Residues in the Core Cytoplasmic and Transmembrane Regions of Multidrug Resistance Protein 1 (MRP1/ABCC1) Important for Transport Function, Substrate Specificity, and Nucleotide Interactions

Koike

Conseil

Leslie

et al. 2004

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-binding cassette transporter that confers resistance to drugs and mediates the transport of organic anions. MRP1 has a core structure of two membrane spanning domains (MSDs) each followed by a nucleotide binding domain. This core structure is preceded by a third MSD with five transmembrane (TM) helices, whereas MSD2 and MSD3 each contain six TM helices. We investigated the consequences of Ala substitution of 18 Pro residues in both the non-membrane and TM regions of MSD2 and MSD3 on MRP1 expression and organic anion transport function. All MRP1-Pro mutants except P1113A were expressed in human embryonic kidney cells at levels comparable with wild-type MRP1. In addition, five mutants containing substitutions of Pro residues in or proximal to the TM helices of MSD2 (TM6-Pro 343 , TM8-Pro 448 , TM10-Pro 557 , and TM11-Pro 595 ) and MSD3 (TM14-Pro 1088 ) exhibited significantly reduced transport of five organic anion substrates. In contrast, mutation of Pro 1150 in the cytoplasmic loop (CL7) linking TM15 to TM16 caused a substantial increase in 17␤-estradiol-17-␤-(D-glucuronide) and methotrexate transport, whereas transport of other organic anions was reduced or unchanged. Significant substrate-specific changes in the ATP dependence of transport and binding by the P1150A mutant were also observed. Our findings demonstrate the importance of TM6, TM8, TM10, TM11, and TM14 in MRP1 transport function and suggest that CL7 may play a differential role in coupling the activity of the nucleotide binding domains to the translocation of different substrates across the membrane.The human MRP1 1 (gene symbol ABCC1) that was originally cloned from a multidrug-resistant small cell lung cancer cell line is an integral membrane protein that belongs to subfamily C of the ABC superfamily of transporter proteins (1-3). The human ABCC subfamily contains nine MRP-related proteins (MRP1-6/ABCC1-6 and MRP7-9/ABCC10 -12), the cystic fibrosis transmembrane conductance regulator (CFTR/ABCC7), and the sulfonylurea receptors SUR1 (ABCC8) and SUR2 (ABCC9) (4, 5). All 12 ABCC members have a core four domain structure consisting of two MSDs (each containing 6 TM helices) and two NBDs configured MSD-NBD1-MSD-NBD2. The core structures of MRP1-3, -6, and -7, as well as SUR1 and SUR2 are connected by a cytoplasmic loop, CL3 (or L o ) to a fifth domain, an NH 2 -terminal MSD consisting of 5 TM helices. This third MSD is the major structural feature that distinguishes these five domain, 17-TM helix proteins from CFTR, MRP4,3,4,6). The precise physiological functions of all ABCC proteins are not yet fully understood, although several are known to be important in certain genetic disorders. For example, mutations in MRP2 (ABCC2) are responsible for Dubin-Johnson syndrome, a form of congenital conjugated hyperbilirubinemia (7), and mutations in CFTR (ABCC7) cause cystic fibrosis (8).Increased expression of MRP1 has been detected in drugresistant tumor cell lines and tumor tissues, and MRP1 has been demo...

show abstract

“…For example, one of the most intensively investigated flavonoids, quercetin, is often just used as the aglycone in cell culture systems and interesting biological activities such as modulation of the multidrug-resistance protein [118], induction of apoptosis [168], inhibition of the expression of nitric oxide synthase and cyclooxygenase [162], protection against oxidative stress [88] and modulation of the calcium homeostasis [209] have been reported. However, in plants and, therefore, also in all plant-derived foods and beverages, quercetin is always present in a glycosylated form which completely alters its bioactivity.…”

Section: Flavonoids: Neuroprotective Agents In Vivo and In Vitro?mentioning

confidence: 99%

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Schroeter

Boyd

Spencer

et al. 2002

Neurobiology of Aging

310

178

View full text Add to dashboard Cite

Oxidative and nitrosative stress is increasingly associated with the pathology of neurodegeneration and aging. The molecular mechanisms underlying oxidative/nitrosative stress-induced neuronal damage are emerging and appear to involve a mode of death in which mitogen-activated protein kinase (MAPK) signaling pathways are strongly implicated. Thus, attention is turning towards the modulation of intracellular signaling as a therapeutic approach against neurodegeneration. Both endogenous and dietary agents have been suggested as potent modulators of intracellular signal transduction, e.g. nitric oxide and flavonoids, respectively. This review addresses recent findings on the biological effects of flavonoids and nitric oxide in neurodegeneration and aims to elucidate the rationale for their prospective use as modulators of cellular signal transduction. © 2002 Elsevier Science Inc. All rights reserved.Keywords: Apoptosis; Oxidative stress; Neuron; Flavonoids; MAP kinase; JNK; ERK; Epicatechin; Nitric oxide; Mitochondria; Redox status; Polyphenols Abbreviations: AKT, serine/threonine kinase (also known as protein kinase B); AP-1, activator protein-1; Apaf-1, apoptosis protease activating factor-1; ASK1, apoptosis signal-regulating kinase-1; Bad, Bcl-2/BclX Lassociated death promoting protein; Bax, pro-apoptotic protein of the Bcl-2 family; Bcl-2, B-cell lymphoma 2: protein with anti-apoptotic properties; BclX L , long form of Bclx: anti-apoptotic protein of the Bcl-2 family; Caspase, cysteinyl aspartic acid-protease; c-Jun, mammalian equivalent of Jun: part of the AP-1 transcription complex; CREB, cAMP response element binding protein; DIABLO/smac, mitochondria-related pro-apoptotic protein: inhibits XIAP; ERK1/2, extracellular signal-related kinase; Fas, CD95: member of the TNF receptor family; GSHST, glutathione Stransferase; JNK, c-Jun amino-terminal kinase; MAPK, mitogen-activated protein kinase; MAPKK, MAPK kinase; MAPKKK, MAPKK kinase; MEK1/2, ERK1/2-specific MAPKK; MKK4/7, JNK-specific MAPKK; MSK1, mitogen-and stress-activated kinase-1; NF-B, nuclear factor of immunoglobulin k locus in B-cells; ONOO − , peroxynitrite anion; p53, pro-apoptotic tumor suppressor gene product; PI3-kinase, phosphoinositol 3-kinase; Ras, small G-protein; RNS, reactive nitrogen species; ROS, reactive oxygen species; RSK, pp90 ribosomal S6 kinase; SAPK, stressactivated protein kinase; XIAP, X-linked inhibitor of apoptosis: inhibits the activation of caspase-9

show abstract

Modulation of Multidrug Resistance Protein 1 (MRP1/ABCC1) Transport and ATPase Activities by Interaction with Dietary Flavonoids

Cited by 216 publications

References 40 publications

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Hepatic Basolateral Efflux Contributes Significantly to Rosuvastatin Disposition I: Characterization of Basolateral Versus Biliary Clearance Using a Novel Protocol in Sandwich-Cultured Hepatocytes

Identification of Proline Residues in the Core Cytoplasmic and Transmembrane Regions of Multidrug Resistance Protein 1 (MRP1/ABCC1) Important for Transport Function, Substrate Specificity, and Nucleotide Interactions

MAPK signaling in neurodegeneration: influences of flavonoids and of nitric oxide

Contact Info

Product

Resources

About