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.
School of Pharmaceutical Sciences, Capital Medical University, Beijing, 100069, China.
Toxicology. 2020 May 15;437:152445. doi: 10.1016/j.tox.2020.152445. Epub 2020 Apr 4.
Organic anion transporting polypeptide 1B1 (OATP1B1), a liver-specific uptake transporter, was associated with drug induced liver injury (DILI). Screening and identifying potent OATP1B1 inhibitors with little toxicity is of great value in reducing OATP1B1-mediated DILI. Flavonoids are a group of polyphenols ubiquitously present in vegetables, fruits and herbal products, some of them were reported to produce transporter-mediated DDI. Our objective was to investigate potential inhibitors of OATP1B1 from 99 flavonoids, and to assess the hepatoprotective effects on bosentan induced liver injury. Eight flavonoids, including biochanin A, hispidulin, isoliquiritigenin, isosinensetin, kaempferol, licochalcone A, luteolin and sinensetin exhibited significant inhibition (>50 %) on OATP1B1 in OATP1B1-HEK293 cells, which reduced the OATP1B1-mediated influx of methotrexate, accordingly decreased its cytotoxicity in OATP1B1-HEK293 cells and increased its AUC in different extents in rats, from 28.27%-82.71 %. In bosentan-induced rat liver injury models, 8 flavonoids reduced the levels of serum total bile acid (TBA) and the liver concentration of bosentan in different degrees. Among them, kaempferol decreased the concentration most significantly, by 54.17 %, which indicated that flavonoids may alleviate bosentan-induced liver injury by inhibiting OATP1B1-mediated bosentan uptake. Furthermore, the pharmacophore model indicated the hydrogen bond acceptors and hydrogen bond donors may play critical role in the potency of flavonoids inhibition on OATP1B1. Taken together, our findings would provide helpful information for predicting the potential risks of flavonoid-containing food/herb-drug interactions in humans and alleviating bosentan -induced liver injury by OATP1B1 regulation.
有机阴离子转运多肽 1B1（OATP1B1）是一种肝脏特异性摄取转运体，与药物性肝损伤（DILI）有关。筛选和鉴定具有低毒性的强效 OATP1B1 抑制剂对于减少 OATP1B1 介导的 DILI 具有重要价值。类黄酮是一组广泛存在于蔬菜、水果和草药产品中的多酚，其中一些被报道会产生转运体介导的 DDI。我们的目的是从 99 种类黄酮中筛选出潜在的 OATP1B1 抑制剂，并评估其对波生坦诱导的肝损伤的保护作用。八种类黄酮，包括大豆素 A、毛地黄黄酮、异甘草素、异甘草素、山奈酚、甘草查尔酮 A、木犀草素和橙皮素，在 OATP1B1-HEK293 细胞中对 OATP1B1 表现出显著的抑制作用（>50%），从而降低了 OATP1B1 介导的甲氨蝶呤内流，相应地降低了其在 OATP1B1-HEK293 细胞中的细胞毒性，并在不同程度上增加了其在大鼠体内的 AUC，范围为 28.27%-82.71%。在波生坦诱导的大鼠肝损伤模型中，八种类黄酮不同程度地降低了血清总胆汁酸（TBA）水平和肝脏中波生坦的浓度。其中，山奈酚降低的浓度最显著，为 54.17%，表明类黄酮可能通过抑制 OATP1B1 介导的波生坦摄取来减轻波生坦诱导的肝损伤。此外，药效基团模型表明氢键受体和氢键供体可能在类黄酮对 OATP1B1 的抑制作用中发挥关键作用。综上所述，我们的研究结果为预测含类黄酮的食物/草药与药物相互作用的潜在风险以及通过 OATP1B1 调节减轻波生坦诱导的肝损伤提供了有价值的信息。
