RT Journal Article
SR Electronic
T1 Interaction of Positional Isomers of Quercetin Glucuronides with the Transporter ABCC2 (cMOAT, MRP2)
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1262
OP 1268
DO 10.1124/dmd.106.014241
VO 35
IS 8
A1 Gary Williamson
A1 Isabelle Aeberli
A1 Laurence Miguet
A1 Ziding Zhang
A1 M.-Belen Sanchez
A1 Vanessa Crespy
A1 Denis Barron
A1 Paul Needs
A1 Paul A. Kroon
A1 H. Glavinas
A1 Peter Krajcsi
A1 Martin Grigorov
YR 2007
UL http://dmd.aspetjournals.org/content/35/8/1262.abstract
AB The exporter ABCC2 (cMOAT, MRP2) is a membrane-bound protein on the apical side of enterocytes and hepatic biliary vessels that transports leukotriene C4, glutathione, some conjugated bile salts, drugs, xenobiotics, and phytonutrients. The latter class includes quercetin, a bioactive flavonoid found in foods such as onions, apples, tea, and wine. There is no available three-dimensional (3D) structure of ABCC2. We have predicted the 3D structure by in silico modeling, showing that 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (MK571) binds most tightly to the putative binding site, and then tested the computational prediction experimentally by measuring interaction with all quercetin monoglucuronides occurring in vivo (quercetin substituted with glucuronic acid at the 3-, 3′-, 4′-, and 7-hydroxyl groups). The 4′-O-β-D-glucuronide is predicted in silico to interact most strongly and the 3-O-β-D-glucuronide most weakly, and this prediction is supported experimentally using binding and competition assays on ABCC2-overexpressing baculovirus-infected Sf9 cells. To test the transport in situ, we examined the effect of two ABCC2 inhibitors, MK571 and cyclosporin A, on the transport into the media of quercetin glucuronides produced intracellularly by Caco2 cells. The inhibitors reduced the amount of all quercetin glucuronides in the media. The results show that the molecular model of ABCC2 agrees well with experimentally determined ABCC2-ligand interactions and, importantly, that the interaction of ABCC2 with quercetin glucuronides is dependent on the position and nature of substitution. The American Society for Pharmacology and Experimental Therapeutics