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.
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 muM and for morin, robinetin and taxifolin between 164 and 268 microM. 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 microM 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.
authors.affiliation: Division of Toxicology, Wageningen University, PO Box 8000, 6700 EA Wageningen, The Netherlands. maaike.schutte@wur.nl
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Schutte
authors.forename: Andreas P
authors.initials: AP
authors.lastname: Freidig
authors.forename: Johannes J M
authors.initials: JJ
authors.lastname: van de Sandt
authors.forename: Gerrit M
authors.initials: GM
authors.lastname: Alink
authors.forename: Ivonne M C M
authors.initials: IM
authors.lastname: Rietjens
authors.forename: John P
authors.initials: JP
authors.lastname: Groten
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000166:Acridines / Q000494:pharmacology; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002273:Carcinogens / Q000378:metabolism*; D002463:Cell Membrane Permeability / Q000187:drug effects; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D044950:Flavanones / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D026901:Membrane Transport Proteins / Q000378:metabolism; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D015203:Reproducibility of Results; D044005:Tetrahydroisoquinolines / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000166:Acridines; D002273:Carcinogens; D044950:Flavanones; D005419:Flavonoids; D007093:Imidazoles; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D011422:Propionates; D011804:Quinolines; D044005:Tetrahydroisoquinolines; C116614:ABCG2 protein, human; C059141:verlukast; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine; C083501:Elacridar; C421109:multidrug resistance-associated protein 1