Effect of bioflavonoids on vincristine transport across blood-brain barrier
Effect of bioflavonoids on vincristine transport across blood-brain barrier
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DOI：
10.1016/s0014-2999(00)00180-1
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发表时间：
2000-05-03
影响因子：
5
通讯作者：
Sawada, Y
中科院分区：
文献类型：
--
作者：
Mitsunaga, Y;Takanaga, H;Sawada, Y
据报道，包括槲皮素在内的几种葡萄柚汁生物素可刺激P-糖蛋白介导的药物从培养的肿瘤细胞中流出。为了观察这些生物活性物质是否改变长春新碱穿过血脑屏障的渗透，我们在体外和体内分别用培养的小鼠脑毛细血管内皮细胞（MBEC 4细胞）和ddY小鼠进行了实验。10 μ M槲皮素可降低MBEC 4细胞对[H-3]长春新碱的稳态摄取，50 μ M槲皮素可增加[H-3]长春新碱的稳态摄取。同样，ddY小鼠中[H-3]长春新碱的体内脑-血浆浓度比在0.1 mg/kg槲皮素联合给药时降低，但在1.0 mg/kg槲皮素联合给药时升高。山奈酚对[H-3]长春新碱的体外摄取具有相似的双相效应。测试的其他苷元（白杨素、黄酮、橙皮素、柚皮素）在10-50 μ M范围内增加[H-3]长春新碱的摄取，而糖苷（橙皮苷、柚皮苷、芦丁）则没有影响。然后，我们讨论了槲皮素的浓度依赖性双相作用的机制。P-糖蛋白抑制剂维拉帕米（Verapamil）抑制[H-3]长春新碱的外排，而10 μ M槲皮素（Quercetin）则明显促进[H-3]长春新碱的外排，蛋白激酶C抑制剂可增加[H-3]长春新碱在MBEC 4细胞中的摄取，而佛波酯（PMA）和10 μ M槲皮素则可降低[H-3]长春新碱在MBEC 4细胞中的摄取。在5 μ M槲皮素或100 nM PMA存在下，P-糖蛋白的磷酸化水平增加，但蛋白激酶C抑制剂H7（1-（5-异喹啉磺酰基）-2-甲基-哌嗪，30 μ M）降低。我们得出结论，低浓度的槲皮素间接激活[H-3]长春新碱的运输，通过增强磷酸化（因此活性）的P-糖蛋白，而高浓度的槲皮素抑制P-糖蛋白。我们的研究结果表明，服用P-糖蛋白底物药物的患者可能需要限制含类生物素的食物和饮料的摄入，如葡萄柚汁。(C)2000 Elsevier Science B. V.保留所有权利。
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 [H-3]vincristine by MBEC4 cells was decreased by 10 mu M quercetin, but increased by 50 mu M quercetin. Similarly, the in vivo brain-to-plasma concentration ratio of [H-3]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 [H-3]vincristine. Other aglycones tested (chrysin, flavon, hesperetin, naringenin) increased [H-3]vincristine uptake in the 10-50 mu M 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 [H-3]vincristine from MBEC4 cells, while 10 mu M quercetin significantly stimulated it. The uptake of [H-3]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 mu M quercetin. The phosphorylation level of P-glycoprotein was increased in the presence of 5 mu M quercetin or 100 nM PMA, but decreased by the protein kinase C inhibitor H7 (1-(5-isoquinolinesulfonyl)-2-methyl-piperazine, 30 mu M). We conclude that low concentrations of quercetin indirectly activate the transport of [H-3]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. All rights reserved.