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Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids

Cellular & Molecular Biology Letters volume 14, pages 199–221 (2009)Cite this article

Abstract

The expression of transmembrane transporter multidrug resistance-associated protein 1 (MRP1) confers the multidrug-resistant phenotype (MDR) on cancer cells. Since the activity of the other MDR transporter, P-glycoprotein, is sensitive to membrane perturbation, we aimed to check whether the changes in lipid bilayer properties induced by flavones (apigenin, acacetin) and flavonols (morin, myricetin) were related to their MRP1 inhibitory activity. All the flavonoids inhibited the efflux of MRP1 fluorescent substrate from human erythrocytes and breast cancer cells. Morin was also found to stimulate the ATPase activity of erythrocyte ghosts. All flavonoids intercalated into phosphatidylcholine bilayers as judged by differential scanning calorimetry and fluorescence spectroscopy with the use of two carbocyanine dyes. The model of an intramembrane localization for flavones and flavonols was proposed. No clear relationship was found between the membrane-perturbing activity of flavonoids and their potency to inhibit MRP1. We concluded that mechanisms other than perturbation of the lipid phase of membranes were responsible for inhibition of MRP1 by the flavonoids.

Abbreviations

BCECF-AM:

2′,7′-bis-(3-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester

BCRP:

breast cancer resistance protein

ΔH:

enthalpy change of the main phospholipid phase transition

DiOC2(3):

3,3′-diethyloxacarbocyanine iodide

DiOC6(3):

3,3′-dihexyloxacarbocyanine iodide

DMPC:

1,2-dimyristoyl-sn-glycero-3-phosphatidylcholine

DPPC:

1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine

EYPC:

egg yolk L-α-phosphatidylcholine

MDR:

multidrug resistance

MRP1:

multidrug resistance-associated protein 1

NBD:

nucleotide binding domain

P-gp:

P-glycoprotein

TM :

temperature of the main phospholipid phase transition

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Authors and Affiliations

  1. Department of Biophysics, Wrocław Medical University, ul. Chałubińskiego 10, 50-368, Wrocław, Poland

    Olga Wesołowska, Andrzej B. Hendrich, Barbara Łania-Pietrzak, Jerzy Wiśniewski & Krystyna Michalak

  2. Institute of Medical Microbiology, University of Szeged, Dom ter 10, H-6720, Szeged, Hungary

    Joseph Molnar

  3. Department of Biochemistry, University of Szeged, Dom ter 9, H-6720, Szeged, Hungary

    Imre Ocsovszki

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  1. Olga Wesołowska
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  2. Andrzej B. Hendrich
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  3. Barbara Łania-Pietrzak
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Correspondence to Olga Wesołowska.

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Wesołowska, O., Hendrich, A.B., Łania-Pietrzak, B. et al. Perturbation of the lipid phase of a membrane is not involved in the modulation of MRP1 transport activity by flavonoids. Cell Mol Biol Lett 14, 199–221 (2009). https://doi.org/10.2478/s11658-008-0044-3

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Cellular & Molecular Biology Letters

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