Mechanism-Based Inhibitory and Peroxisome Proliferator-Activated Receptor α–Dependent Modulating Effects of Silybin on Principal Hepatic Drug-Metabolizing Enzymes

Abstract

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)a, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARa by fenofibrate, characterized with significantly repressed expression of PPARa 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 PPARa agonists via the repression of PPARa activation in a competitive mode.

Silibinin affects the pharmacokinetics of methadone in rats

“…Silibinin is a well‐known hepatoprotective compound extracted from milk thistle . Reported studies have demonstrated that silibinin inhibited multiple drug‐metabolizing enzymes and confer drug–drug interactions with concomitant drugs …”

“…17 Reported studies have demonstrated that silibinin inhibited multiple drug-metabolizing enzymes and confer drug-drug interactions with concomitant drugs. 21,22 Silibinin is both a substrate and inhibitor of P-gp, also known as ABCB1 (ATP-binding cassette sub-family B member 1). 23 It has been demonstrated that the polymorphism of ABCB1 C3435T significantly influenced the pharmacokinetics of silibinin in healthy volunteers by increasing its peak plasma concentration and AUC.…”

SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis

“…Western blot analysis. Western blot analysis was conducted with standard method as previously described 65 . Briefly, protein lysates were separated by SDS-PAGE and transferred to a PVDF membrane, which was then blocked in 5% nonfat milk.…”

“…Reporter gene analysis. Cells were transfected with Plin1 luciferase reporter constructs using Lipofectamine 2000 reagent according to the manual instruction and treated with OCA in the absence or presence of SP for 24 h. Cells were lysed and the luciferase activities were measured with the Luc-Pair Duo-Luciferase HS Assay Kit (GeneCopoeia, Rockville, MD, USA) 65 .…”

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“…Ґени, які кодують синтез ґлутатіон-S-трансфераз (GST), належать до основних, залучених у патоґенез різних хронічних дифузних захворювань печінки (ХДЗП) [40,65]. На адипо-та фіброґенез впливають також ґени, що кодують синтез рецепторів-активаторів проліферації пероксисом (PPAR) [67,71], які відіграють ключову роль у моделюванні синтезу, депонування і транспортування ліпідів і здатні впливати на виникнення й перебіг НАЖХП [36].…”