Modulation of MRP1 protein transport by plant, and synthetically modified flavonoids.
The influence of novel synthetic and plant origin flavonoids on activity of multidrug resistance-associated protein (MRP1) was investigated in human erythrocytes used as a cell model expressing MRP1 in plasma membrane. The fluorescent probe, BCPCF (2', 7'-bis-(3-carboxy-propyl)-5-(and-6)-carboxyfluorescein), was applied as a substrate for MRP1 multidrug resistance transporter. The effect of compounds belonging to different classes of natural flavonoids: flavone, flavonol, isoflavones and flavanolignan was compared with action of new synthetic derivatives of genistein. Most of the flavonoids showed strong or moderate ability to inhibit transport carried out by MRP1. Inhibitory properties of flavonoids were compared to the effects of indomethacin, probenecid and MK-571 known as MRP1 inhibitors. Studying the influence of new synthetic genistein derivatives on BCPCF transport we have found that the presence of hydrophobic groups substituting hydrogen of hydroxyl group at the position 4' in ring B of isoflavone is more important for inhibitory properties than hydrophobic substitution at the position 7 in ring A. In case of naturally occurring isoflavones the replacement of hydrogen at position 4' by hydrophobic ring structure seems also to be favourable for inhibition potency.
Łania-Pietrzak
Barbara
B
Department of Biophysics, Wrocław Medical University, Chałubińskiego 10, 50-368 Wrocław, Poland.
Michalak
Krystyna
K
Hendrich
Andrzej B
AB
Mosiadz
Daniela
D
Grynkiewicz
Grzegorz
G
Motohashi
Noboru
N
Shirataki
Yoshiaki
Y
D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology*; D005452:Fluoresceins / Q000378:metabolism; D019833:Genistein / Q000031:analogs & derivatives / Q000494:pharmacology; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D010944:Plants / Q000737:chemistry*; D011422:Propionates / Q000494:pharmacology; D021381:Protein Transport / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology; D047309:Flavones
D005419:Flavonoids; D005452:Fluoresceins; D019833:Genistein; D007213:Indomethacin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011422:Propionates; D011804:Quinolines; D000077385:Silybin; D012838:Silymarin; C473073:2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein; C059141:verlukast; C008548:morin; D047309:Flavones; C421109:multidrug resistance-associated protein 1