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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

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Author: Schutte, M.E. · Freidig, A.P. · Sandt, J.J.M. van de · Alink, G.M. · Rietjens, I.M.C.M. · Groten, J.P.
Type:article
Date:2006
Institution: TNO Kwaliteit van Leven
Source:Toxicology and Applied Pharmacology, 2, 217, 204-215
Identifier: 239640
doi: doi:10.1016/j.taap.2006.08.005
Keywords: 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

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.