Title
An in vitro and in silico study on the flavonoid-mediated modulation of the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers
Author
Schutte, M.E.
Freidig, A.P.
van de Sandt, J.J.M.
Alink, G.M.
Rietjens, I.M.C.M.
Groten, J.P.
TNO Kwaliteit van Leven
Publication year
2006
Abstract
The present study describes the effect of different flavonoids on the absorption of the pro-carcinogen PhIP through Caco-2 monolayers and the development of an in silico model describing this process taking into account passive diffusion and active transport of PhIP. Various flavonoids stimulated the apical to basolateral PhIP transport. Using the in silico model for flavone, kaempferol and chrysoeriol, the apparent Ki value for inhibition of the active transport to the apical side was estimated to be below 53 μM and for morin, robinetin and taxifolin between 164 and 268 μM. For myricetin, luteolin, naringenin and quercetin, the apparent Ki values were determined more accurately and amounted to 37.3, 12.2, 11.7 and 5.6 μM respectively. Additional experiments revealed that the apical to basolateral PhIP transport was also increased in the presence of a typical BCRP or MRP inhibitor with apparent Ki values in the same range as those of the flavonoids. This observation together with the fact that flavonoids are known to be inhibitors of MRPs and BCRP, corroborates that inhibition of these apical membrane transporters is involved in the flavonoid-mediated increased apical to basolateral PhIP transport. Based on the apparent Ki values obtained, it is concluded that the flavonols, at the levels present in the regular Western diet, are capable of stimulating the transport of PhIP through Caco-2 monolayers from the apical to the basolateral compartment. This points to flavonoid-mediated stimulation of the bioavailability of PhIP and, thus, a possible adverse effect of these supposed beneficial food ingredients. © 2006 Elsevier Inc. All rights reserved.
Subject
Biology
Biomedical Research
ABC transporter
Caco-2
Flavonoid
Heterocyclic amine
In silico
2 amino 1 methyl 6 phenylimidazo[4,5 b]pyridine
breast cancer resistance protein
chrysoeriol
elacridar
flavone
flavonoid
kaempferol
luteolin
morin
multidrug resistance protein
myricetin
naringenin
quercetin
robinetin
taxifolin
unclassified drug
verlukast
absorption
apical membrane
article
cell strain CACO 2
computer model
controlled study
drug effect
human
human cell
Acridines
ATP-Binding Cassette Transporters
Biological Transport, Active
Caco-2 Cells
Carcinogens
Cell Membrane Permeability
Diffusion
Dose-Response Relationship, Drug
Flavanones
Flavonoids
Humans
Imidazoles
Intestinal Absorption
Intestinal Mucosa
Kinetics
Membrane Transport Proteins
Models, Biological
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
P-Glycoprotein
Propionates
Quinolines
Reproducibility of Results
Tetrahydroisoquinolines
To reference this document use:
http://resolver.tudelft.nl/uuid:e2be7c1d-a09d-47b4-9964-e38d1c9d90e9
DOI
https://doi.org/10.1016/j.taap.2006.08.005
TNO identifier
239640
ISSN
0041-008X
Source
Toxicology and Applied Pharmacology, 217 (2), 204-215
Document type
article