Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2

Autor: Zanden, J.J. van, Wortelboer, H.M., Bijlsma, S., Punt, A., Usta, M., Bladeren, P.J.V., Rietjens, I.M.C.M., Cnubben, N.H.P.
Přispěvatelé: TNO Kwaliteit van Leven
Jazyk: angličtina
Rok vydání: 2005
Předmět:
flavone
Quantitative Structure-Activity Relationship
robinetin
animal cell
3
3'
4' trihydroxyflavone
quercetin
taxifolin
chrysin
myricetin
4' hydroxyflavone
acacetin
3 hydroxyflavone
heterocyclic compounds
multidrug resistance protein 1
multidrug resistance protein 2
QSAR
MRP2
drug effect
article
quantitative structure activity relation
3
3' dihydroxyflavone
galangin
3'
4' dihydroxyflavone
Fluoresceins
unclassified drug
priority journal
MRP1
Multidrug Resistance-Associated Proteins
3' hydroxyflavone
drug potency
baicalein
cell kinetics
fisetin
naringenin
kaempferide
Cell Line
cell transport
Dogs
catechin
Membrane Transport Modulators
Nutrition Pharmacology
valspodar
unindexed drug
Animals
flavonoid
controlled study
luteolin
drug inhibition
drug selectivity
Analytical research
Flavonoids
apigenin
kaempferol
nonhuman
Membrane Transport Proteins
IC 50
morin
5
7
3'
4' tetramethoxyflavone
protein inhibitor
verlukast
protein analysis
Calcein
genetic transfection
Popis: In the present study, the effects of a large series of flavonoids on multidrug resistance proteins (MRPs) were studied in MRP1 and MRP2 transfected MDCKII cells. The results were used to define the structural requirements of flavonoids necessary for potent inhibition of MRP1- and MRP2-mediated calcein transport in a cellular model. Several of the methoxylated flavonoids are among the best MRP1 inhibitors (IC50 values, ranging between 2.7 and 14.3 μM) followed by robinetin, myricetin and quercetin (IC50 values ranging between 13.6 and 21.8 μM). Regarding inhibition of MRP2 activity especially robinetin and myricetin appeared to be good inhibitors (IC 50 values of 15.0 and 22.2 μM, respectively). Kinetic characterization revealed that the two transporters differ marginally in the apparent Km for the substrate calcein. For one flavonoid, robinetin, the kinetics of inhibition were studied in more detail and revealed competitive inhibition with respect to calcein, with apparent inhibition constants of 5.0 μM for MRP1 and 8.5 μM for MRP2. For inhibition of MRP1, a quantitative structure activity relationship (QSAR) was obtained that indicates three structural characteristics to be of major importance for MRP1 inhibition by flavonoids: the total number of methoxylated moieties, the total number of hydroxyl groups and the dihedral angle between the B- and C-ring. Regarding MRP2 mediated calcein efflux inhibition, only the presence of a flavonol B-ring pyrogallol group seems to be an important structural characteristic. Overall, this study provides insight in the structural characteristics involved in MRP inhibition and explores the differences between inhibitors of these two transporters, MRP1 and MRP2. Ultimately, MRP2 displays higher selectivity for flavonoid type inhibition than MRP1. © 2004 Elsevier Inc. All rights reserved.
Databáze: OpenAIRE
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