Effect of bioflavonoids on vincristine transport across blood-brain barrier

Yoshiharu Mitsunaga, Hitomi Takanaga, Hirotami Matsuo, Mikihiko Naito, Takashi Tsuruo, Hisakazu Ohtani, Yasufumi Sawada

研究成果: Article査読

145 被引用数 (Scopus)

抄録

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 μM quercetin, but increased by 50 μM 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 μM 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 μM 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 μM quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 μM quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5- isoquinolinesulfonyl)-2-methylpiperazine, 30 μM). 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. (C) 2000 Elsevier Science B.V.

本文言語English
ページ(範囲)193-201
ページ数9
ジャーナルEuropean journal of pharmacology
395
3
DOI
出版ステータスPublished - 2000 5 3
外部発表はい

ASJC Scopus subject areas

  • 薬理学

フィンガープリント

「Effect of bioflavonoids on vincristine transport across blood-brain barrier」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル