State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of Drug Metabolism, Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Beijing Key Laboratory of Active Substances Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.
Toxicol In Vitro. 2019 Dec;61:104642. doi: 10.1016/j.tiv.2019.104642. Epub 2019 Sep 5.
Flavonoids are a group of polyphenols ubiquitously present in vegetables, fruits and herbal products, despite various known pharmacological activities, few researches have been done about the interaction of flavonoids with breast cancer resistance protein (BCRP). The present study was designed to investigate the inhibitory effects of 99 flavonoids on BCRP in vitro and in vivo and to clarify structure-activity relationships of flavonoids with BCRP. Eleven flavonoids, including amentoflavone, apigenin, biochanin A, chrysin, diosimin, genkwanin, hypericin, kaempferol, kaempferide, licochalcone A and naringenin, exhibited significant inhibition (>50%) on BCRP in BCRP-MDCKII cells, which reduced the BCRP-mediated efflux of doxorubicin and temozolomide, accordingly increased their cytotoxicity. In addition, co-administration of mitoxantrone with the 11 flavonoids increased the AUC of mitoxantrone in different extents in rats. Among them, chrysin increased the AUC most significantly, by 81.97%. Molecular docking analysis elucidated the inhibition of flavonoids on BCRP might be associated with Pi-Pi stacked interactions and/or potential Pi-Alkyl interactions, but not conventional hydrogen bonds. The pharmacophore model indicated the aromatic ring B, hydrophobic groups and hydrogen bond acceptors may play critical role in the potency of flavonoids inhibition on BCRP. Thus, our findings would provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans.
类黄酮是广泛存在于蔬菜、水果和草药产品中的一类多酚，尽管具有多种已知的药理学活性，但对类黄酮与乳腺癌耐药蛋白（BCRP）的相互作用研究甚少。本研究旨在体外和体内研究 99 种类黄酮对 BCRP 的抑制作用，并阐明类黄酮与 BCRP 的构效关系。11 种类黄酮，包括芹菜素、芹菜素、大豆素 A、白杨素、大豆苷元、圣草酚、金丝桃素、山奈酚、山奈酚、甘草素 A 和柚皮素，在 BCRP-MDCKII 细胞中对 BCRP 表现出显著的抑制作用（>50%），从而减少了 BCRP 介导的阿霉素和替莫唑胺的外排，相应地增加了它们的细胞毒性。此外，米托蒽醌与 11 种类黄酮共同给药可在不同程度上增加米托蒽醌在大鼠中的 AUC。其中，白杨素增加的 AUC 最为显著，增加了 81.97%。分子对接分析表明，类黄酮对 BCRP 的抑制作用可能与π-π堆积相互作用和/或潜在的π-烷基相互作用有关，但与常规氢键无关。药效团模型表明，芳香环 B、疏水区和氢键受体可能在类黄酮抑制 BCRP 的效力中起关键作用。因此，我们的研究结果将为预测含类黄酮的食物/草药与药物相互作用对人类的潜在风险提供有价值的信息。
