水飞蓟宾对硫代乙酰胺所致肝损伤状态下CYP3A的调节作用及机制(英文)  

Reversing effects of silybin on TAA-induced hepatic CYP3A dysfunction through PXR regulation

作　　者：谢媛[1] 郝海平[2] 王洪[2] 王兆先[3] 王广基[2] 

机构地区：[1]中国药科大学中药药理教研室,南京210009 [2]中国药科大学天然药物活性组分与药效国家重点实验室,药代动力学重点实验室,南京210009 [3]中国药科大学药学院,南京210009

出　　处：《中国天然药物》2013年第6期645-652,共8页

基　　金：supported by the National Natural Science Foundation of China(Nos.81273586,91029746,81202590);the Natural Science Foundation of Jiangsu Province ofChina(No.SBK201240817);the Fundamental Research Funds for the Central Universities(No.JKQ2011040)~~

摘　　要：目的:水飞蓟宾(SB)是植物奶蓟的主要成分,长期以来被用于治疗各种肝脏疾病。由于肝病往往伴随有CYP450酶的功能失调,因此本文以硫代乙酰胺(TAA)引起的大鼠肝损伤为模型,研究水飞蓟宾的肝保护作用和对CYP3A的调控作用之间的关系。方法:血清生化指标检测和肝脏病理切片实验评价水飞蓟宾的保肝作用。免疫组化实验测定α-SMA的表达,ELISA试剂盒测定大鼠肝脏炎症因子的表达。实时定量PCR和western blot实验考察CYP3A和PXR的mRNA和蛋白表达水平变化,咪达唑仑4-羟基化反应测定CYP3A的活性。siRNA转染实验沉默PXR后考察PXR在硫代乙酰胺细胞毒和CYP3A调节中的作用。结果:水飞蓟宾表现出明显的保肝、抗炎、抗纤维化作用,并能有效逆转硫代乙酰胺导致的大鼠肝脏CYP3A和PXR表达减少以及PXR的入核减少。PXR沉默实验显示PXR参与了水飞蓟宾的细胞保护和CYP3A调控过程。结论:PXR是参与CYP3A调控的重要因子,很可能是水飞蓟宾在硫代乙酰胺导致的大鼠肝损伤模型中的作用靶点,同时也提示在治疗肝脏疾病时要注意与水飞蓟宾合用的药物可能与水飞蓟宾之间存在潜在的药物相互作用。AIM： Silybin （SB）, a major constituent of the milk thistle, has been used to treat several liver disorders. However, liver diseases were always accompanied by CYP450 dysfunction. This study was designed to explore the relationship between the hepato- protective effect and CYP3A regulation of SB during thioacetamide （TAA）-induced rat liver injury. METHODS： Serum biochemical analysis and histopathological study were taken to evaluate the hepatoprotectinve effect of SB. a-SMA were detected by immunohisto- chemical analysis and cytokine release in rat liver was determined by ELISA assay. CYP3A and PXR expression were determined by RT-PCR and Western blot analysis, and CYP3A activity was based on the midazolam 4-hydroxylation reaction. Also, siRNA transfec- tion was induced in HepG2 cells to evaluate the effect of PXR on cytotoxicity and CYP3A4 dysregulation caused by TAA. RESULTS： SB showed powerful hepatoprotectlve effects, and anti-inflammatory and anti-fibrosis effects, and reversed the loss of CYP3A and PXR in TAA-injured rat liver, and decreased PXR translocation into the cell nucleus. PXR silencing weakened the effect of SB on cytoprotection and CYP3A regulation. CONCLUSIONS： PXR was a very important factor of CYP3A regulation and might be the target of SB in TAA-induced liver disease. Also, because of the potential interactions of SB and co-administered medicines, it might be necessary to adjust the dosage in the clinical medication of liver disease.

关 键 词：水飞蓟宾 硫代乙酰胺 肝损伤 炎症 CYP3A PXR 

分 类 号：R-05[医药卫生]