title: Plant polyphenols and multidrug resistance: effects of dietary flavonoids on drug transporters in Caco-2 and MDCKII-MDR1 cell transport models.
abstract: The hypothesis tested was that specific flavonoids such as epicatechin gallate, epigallocatechin gallate, genistein, genistin, naringenin, naringin, quercetin and xanthohumol will modulate cellular uptake and permeability (P(e)) of multidrug-resistant substrates, cyclosporin A (CSA) and digoxin, across Caco-2 and MDCKII-MDR1 cell transport models. (3)H-CSA/(3)H-digoxin transport and uptake experiments were performed with and without co-exposure of the flavonoids. Aglycone flavonoids reduced the P(e) of CSA to a greater extent than glycosylated flavonoids with 30 microM xanthohumol producing the greatest effect (7.2 x 10(-6) to 6.6 x 10(-7) and 17.9 x 10(-6) to 4.02 x 10(-6) cm s(-1) in Caco-2 and MDCKII-MDR1 cells, respectively); while no measurable effects were seen with digoxin. Xanthohumol significantly demonstrated (1) saturable efflux, (2) increased uptake of (3)H-digoxin and (3) decreased uptake of (3)H-CSA in the Caco-2 cells. The transport data suggests that xanthohumol effects transport of CSA in a manner that is distinct from the digoxin efflux pathway and suggests that intestinal transport of these MDR1 substrates is more complex than previously reported.
authors.affiliation: Department of Pharmaceutical Sciences, Oregon State University, Corvallis, 97331-3507, USA. rosita.proteau@oregonstate.edu
authors.forename: R
authors.initials: R
authors.lastname: Rodriguez-Proteau
authors.forename: J E
authors.initials: JE
authors.lastname: Mata
authors.forename: C L
authors.initials: CL
authors.lastname: Miranda
authors.forename: Y
authors.initials: Y
authors.lastname: Fan
authors.forename: J J
authors.initials: JJ
authors.lastname: Brown
authors.forename: D R
authors.initials: DR
authors.lastname: Buhler
mesh_terms: D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D018938:Caco-2 Cells; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects* / Q000378:metabolism*; D016572:Cyclosporine / Q000493:pharmacokinetics*; D004077:Digoxin / Q000493:pharmacokinetics*; D004285:Dogs; D018432:Drug Resistance, Multiple / Q000187:drug effects; D005419:Flavonoids / Q000008:administration & dosage*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D008657:Metabolic Clearance Rate / Q000187:drug effects; D009747:Nutritional Physiological Phenomena; D010944:Plants / Q000378:metabolism*
chemical_list: D005419:Flavonoids; D004077:Digoxin; D016572:Cyclosporine