Effect of bioflavonoids on vincristine transport across blood-brain barrier

Eur J Pharmacol. 2000 May 3;395(3):193-201. doi: 10.1016/s0014-2999(00)00180-1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-O-Methylglucose / pharmacokinetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Animals
  • Biological Transport
  • Blood-Brain Barrier / drug effects*
  • Brain / drug effects
  • Brain / metabolism
  • Carbon Radioisotopes
  • Cell Line
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Flavonoids / pharmacology*
  • Kaempferols*
  • Mice
  • Phenylalanine / pharmacokinetics
  • Phosphorus Radioisotopes
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Quercetin / analogs & derivatives
  • Quercetin / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Tritium
  • Vincristine / blood
  • Vincristine / pharmacokinetics*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Carbon Radioisotopes
  • Flavonoids
  • Kaempferols
  • Phosphorus Radioisotopes
  • Tritium
  • 3-O-Methylglucose
  • Phenylalanine
  • Vincristine
  • kaempferol
  • Quercetin
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate