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 AUC0-t 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.
Keywords: DILI; Flavonoids; Inhibition; OATP1B1; Structure-activity relationships.
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