不同剂量和疗程栀子苷调控慢性胆汁淤积的疗效/肝毒性效应机制  

Efficacy/hepatoxicity mechanism of geniposide with different doses and courses in the regulation of chronic cholestasis

作　　者：杜曾 邱剑楠 郭真 王伊雯 戚莉 刘佳 王晓柠 DU Zeng;QIU Jian-nan;GUO Zhen;WANG Yi-wen;QI Li;LIU Jia;WANG Xiao-ning(Institute of Interdisciplinary Integrative Medicine Research,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China)

机构地区：[1]上海中医药大学交叉科学研究院,上海201203

出　　处：《中华中医药杂志》2022年第7期4048-4053,共6页China Journal of Traditional Chinese Medicine and Pharmacy

基　　金：国家自然科学基金面上项目(No.81774196)。

摘　　要：目的:探究不同剂量和疗程栀子苷调控慢性胆汁淤积的疗效/肝毒性关系,解析其肝保护及肝损伤效应机制。方法:80只Wistar大鼠随机分为正常组,模型组,栀子苷低、中、高剂量(55、110、220 mg/kg)组。采用ANIT灌胃12周诱导慢性胆汁淤积大鼠模型,于第9周给予对应剂量栀子苷灌胃,每日1次,分别于干预7、28 d采集标本。观察肝、回肠组织病理学改变;Western blot法检测血清肝功能及肝组织BSEP、NTCP、MRP3、MRP4、FXR、CAR及回肠组织ZO-1、Occludin蛋白表达。结果:与模型组比较,桅子苷低剂量组给药7、28 d,大鼠血清ALT、AST、TBA水平均降低(P<0.01,P<0.05);给药7 d,回肠组织固有层水肿和炎症细胞浸润减轻,回肠组织ZO-1、Occludin和肝组织BSEP蛋白表达升高(P<0.01);给药28 d,回肠组织ZO-1、Occludin蛋白表达降低(P<0.05,P<0.01)。栀子苷中、高剂量组给药7、28 d,血清TBIL、DBIL和GGT水平均升高(P<0.05,P<0.01),肝、回肠组织病理损伤加重;给药28 d回肠组织ZO-1、Occludin及肝组织BSEP、FXR、CAR蛋白表达降低(P<0.05,P<0.01),MRP4蛋白表达升高(P<0.05,P<0.01)。栀子苷高剂量组给药7、28 d,血清ALB含量均降低(P<0.01);给药28 d,血清ALT、AST活性升高(P<0.05)。结论:不同剂量和疗程栀子苷调控慢性胆汁淤积产生疗效和肝毒性差异的效应机制,与肠黏膜屏障和肝细胞转运功能损伤密切相关。Objective: To explore the efficacy/hepatotoxicity of geniposide with different doses and courses in regulating chronic cholestasis, and to analyze the hepatoprotective or hepatotoxicity mechanism of geniposide. Methods: Eighty Wistar rats were randomly divided into normal group, model group, geniposide low, medium and high-dose(55, 110, 220 mg/kg) group. The chronic intrahepatic cholestasis rats model was treated with ANIT for 12 weeks. On the first day of the 9th week of modeling,the rats in each treatment group were given the corresponding drug once a day, and the samples were collected on the 7th day and the 28th day after drug intervention. The histopathological changes of liver and ileum were observed. The liver function was tested. The protein expressions of BSEP, NTCP, MRP3, MRP4, FXR, CAR in liver, ZO-1 and Occludin in ileum were detected by Western blot. Results: Compare with model group, in geniposide low-dose group, after administration for 7 days and 28 days, the levels of ALT, AST and TBA in serum were significantly decreased(P<0.01, P<0.05);after 7 days of administration, the edema and inflammatory cell infiltration in the lamina propriety of ileum were decreased, and the expression of ZO-1, Occludin in ileum and BSEP in liver increased(P<0.01);after 28 days of administration, the expression of ZO-1 and Occludin protein in ileum of model rats was decreased(P<0.05, P<0.01). In geniposide medium and high-dose group, after administration for 7 days and 28days, the levels of TBIL, DBIL, and GGT in serum were increased(P<0.05, P<0.01), the pathological damage of liver and ileum was aggravated;after 28 days of administration, the protein expressions of ZO-1, Occludin in ileum, BSEP, FXR and CAR in liver were decreased(P<0.05, P<0.01), and the protein expression of MRP4 in liver was increased(P<0.05, P<0.01). In geniposide high-dose group, after administration for 7 days and 28 days, the content of ALB in serum was decreased(P<0.01);after 28 days of administration, the activities of ALT and AST in serum we

关 键 词：栀子苷 胆汁淤积 剂量-时间-疗效 肝毒性 肠黏膜屏障 肝细胞转运 

分 类 号：R285.5[医药卫生—中药学]