PT  - JOURNAL ARTICLE
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
TI  - Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor <em>α</em>–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes
AID  - 10.1124/dmd.114.061622
DP  - 2015 Apr 01
TA  - Drug Metabolism and Disposition
PG  - 444--454
VI  - 43
IP  - 4
4099  - http://dmd.aspetjournals.org/content/43/4/444.short
4100  - http://dmd.aspetjournals.org/content/43/4/444.full
SO  - Drug Metab Dispos2015 Apr 01; 43
AB  - 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.