TY - JOUR T1 - Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor <em>α</em>–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 444 LP - 454 DO - 10.1124/dmd.114.061622 VL - 43 IS - 4 AU - Hong Wang AU - Tingting Yan AU - Yuan Xie AU - Min Zhao AU - Yuan Che AU - Jun Zhang AU - Huiying Liu AU - Lijuan Cao AU - Xuefang Cheng AU - Yang Xie AU - Feiyan Li AU - Qu Qi AU - Guangji Wang AU - Haiping Hao Y1 - 2015/04/01 UR - http://dmd.aspetjournals.org/content/43/4/444.abstract N2 - Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)α, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARα by fenofibrate, characterized with significantly repressed expression of PPARα targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPARα agonists via the repression of PPARα activation in a competitive mode. ER -