title: Effect of bioflavonoids on vincristine transport across blood-brain barrier.
abstract: Several grapefruit juice bioflavonoids, including quercetin, are reported to stimulate P-glycoprotein-mediated drug efflux from cultured tumor cells. To see whether these bioflavonoids alter the permeation of vincristine across the blood-brain barrier, we conducted experiments with cultured mouse brain capillary endothelial cells (MBEC4 cells) in vitro and ddY mice in vivo. The steady-state uptake of [3H]vincristine by MBEC4 cells was decreased by 10 microM quercetin, but increased by 50 microM quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [3H]vincristine in ddY mice was decreased by coadministration of 0.1 mg/kg quercetin, but increased by 1.0 mg/kg quercetin. Kaempferol had a similar biphasic effect on the in vitro uptake of [3H]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [3H]vincristine uptake in the 10-50 microM range, and glycosides (hesperidin, naringin, rutin) were without effect. We then addressed the mechanism of the concentration-dependent biphasic action of quercetin. Verapamil, a P-glycoprotein inhibitor, inhibited the efflux of [3H]vincristine from MBEC4 cells, while 10 microM quercetin significantly stimulated it. The uptake of [3H]vincristine by MBEC4 cells was increased by inhibitors of protein kinase C, but decreased by phorbol 12-myristate-13-acetate (PMA), as well as by 10 microM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 microM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5-isoquinolinesulfonyl)-2-methylpiperazine, 30 microM). We conclude that low concentrations of quercetin indirectly activate the transport of [3H]vincristine by enhancing the phosphorylation (and hence activity) of P-glycoprotein, whereas high concentrations of quercetin inhibit P-glycoprotein. Our results indicate that patients taking drugs which are P-glycoprotein substrates may need to restrict their intake of bioflavonoid-containing foods and beverages, such as grapefruit juice.
authors.affiliation: Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Mitsunaga
authors.forename: H
authors.initials: H
authors.lastname: Takanaga
authors.forename: H
authors.initials: H
authors.lastname: Matsuo
authors.forename: M
authors.initials: M
authors.lastname: Naito
authors.forename: T
authors.initials: T
authors.lastname: Tsuruo
authors.forename: H
authors.initials: H
authors.lastname: Ohtani
authors.forename: Y
authors.initials: Y
authors.lastname: Sawada
mesh_terms: D019325:3-O-Methylglucose / Q000493:pharmacokinetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology*; D044949:Kaempferols; D051379:Mice; D010649:Phenylalanine / Q000493:pharmacokinetics; D010761:Phosphorus Radioisotopes; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011794:Quercetin / Q000031:analogs & derivatives / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014316:Tritium; D014750:Vincristine / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002250:Carbon Radioisotopes; D005419:Flavonoids; D044949:Kaempferols; D010761:Phosphorus Radioisotopes; D014316:Tritium; D019325:3-O-Methylglucose; D010649:Phenylalanine; D014750:Vincristine; C006552:kaempferol; D011794:Quercetin; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate