Evaluation of inhibitory effects of flavonoids on breast cancer resistance protein (BCRP): From library screening to biological evaluation to structure-activity relationship. (December 2019)

• Record Type: Journal Article
• Authors: Fan, Xiaoqing; Bai, Jie; Zhao, Shengyu; Hu, Minwan; Sun, Yanhong; Wang, Baolian; Ji, Ming; Jin, Jing; Wang, Xiaojian; Hu, Jinping; Li, Yan
• Is Part Of: Toxicology in vitro. Volume 61(2019)
• Publication Date: 2019-12
• Subjects: BCRP -- Flavonoids -- Inhibition -- Molecular mechanism -- Structure-activity relationships; AUC The area under the concentration-time curve -- BCRP Breast cancer resistance protein -- Cmax The maximum plasma concentration -- CMC Carboxymethylcellulose -- DDIs Drug-drug interactions -- DMEM Dulbecco's modified eagle's medium -- FBS Fetal bovine serum -- HBSS Hanks' balanced salt solution -- HPLC High-performance liquid chromatography -- MDR Multi-drug resistance -- MS/MS Tandem mass spectrometry -- TCM Traditional Chinese medicine -- TMZ Temozolomide -- MTT 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- t1/2 Terminal half-life; Toxicity testing -- In vitro -- Periodicals; Toxicology -- Periodicals; 615.9
• DOI: 10.1016/j.tiv.2019.104642
• Languages: English
• ISSNs: 0887-2333

Abstract

Abstract: 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 AUC0−t of mitoxantrone in different extents in rats. Among them, chrysin increased the AUC0−t 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. Highlights: Regulation on Breast cancer resistance protein by 99 flavonoids was systematically investigated. The inhibitory effects were further evaluated in cell toxicity and rat pharmacokinetics study. Molecular docking assays illuminate the inhibitory mechanism. Structure-activity relationships model was constructed to optimize flavonoid inhibitors.