利福平对小鼠的肝毒性及胆酸代谢基因的影响  

Effects of rifampicin on hepatotoxicity and genes related to bile acid metabolism in mice

作　　者：徐永吉[1] 李文楷[1] 刘杰[1] 陆远富[1] 

机构地区：[1]遵义医学院基础药理省部共建教育部重点实验室,贵州遵义563000

出　　处：《中国药理学通报》2016年第6期841-845,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(81460632)

摘　　要：目的观察利福平长期给药引起小鼠的肝损伤及其对胆汁酸代谢通路相关基因的影响。方法 1 d 1次灌胃给予♂昆明种小鼠180 mg·kg^(-1)利福平连续30 d与90 mg·kg^(-1)利福平连续90 d;麻醉取血、肝脏,称肝重,检测血清谷丙转氨酶(ALT),观察肝脏组织的病理变化;提取肝脏总RNA并采用RT-PCR法检测胆汁酸代谢相关基因mRNA的表达情况,提取肝脏总蛋白并采用Western blot法检测相关蛋白的表达。结果连续给予利福平180 mg·kg^(-1)30 d和90 mg·kg^(-1)90 d,小鼠肝重系数增加,肝脏发生明显病理改变,表现为肝细胞水肿、羽毛样变性与脂肪变性,且利福平180 mg·kg^(-1)30 d病理改变较严重;连续给药180 mg·kg^(-1)利福平30 d可使胆酸代谢基因胆固醇7α-羟化酶(CYP7A1)、法尼醇受体(FXR)、小分子异源二聚体伴侣(SHP)表达增加,胆盐输出泵(BSEP)的表达降低;连续给药90 mg·kg^(-1)利福平90 d,仅可发现胆酸代谢基因胆固醇7α-羟化酶(CYP7A1)表达增加。结论利福平对小鼠具有明显肝毒性,引起胆汁淤积性肝损伤;其影响CYP7A1与BSEP的基因表达可能是其导致胆汁淤积性肝损伤的机制之一。Aim To examine liver damage by rifampicin and hepatic gene expression related to bile acid metabolism in mice. Methods Adult male mice were given rifampicin( 180 mg·kg^(-1),po) daily for 30 days and( 90 mg·kg^(-1),po) daily for 90 days,blood biochemistry,histopathology,and gene expression were examined. Results Rifampicin increased animal liver index and serum enzyme activities. Histopathology showed steatosis and spotted feathery-like degeneration. Rifampicin increased the expression of CYP7A1 after 30 and 90 days of administration,along with increased FXR and SHP. Rifampicin reduced the expression of BSEP after 30 days of high dose administration.Conclusion Repeated administration of rifampicin may cause liver injury and intrahepatic cholestasis in mice,and these effects are associated with the alteration of gene expression related to bile acid metabolism.

关 键 词：利福平 肝毒性 胆酸代谢 胆汁淤积 CYP7A1 BSEP 

分 类 号：Q-485[生物学] R-332[医药卫生]