不同抗结核药物致肝损伤小鼠模型的特征指标分析  

Analysis of Characteristic Indexes of Liver Injury Model Induced by Different Antituberculosis Drugs in Mice

作　　者：陆霓虹 刘洪璐 陈杨君 刘梅艳 杨永锐 杜映荣 LU Nihong;LIU Honglu;CHEN Yangjun;LIU Meiyan;YANG Yongrui;DU Yingrong(The Third People’s Hospital of Kunming,Yunnan Provincial Clinical Medical Center for Infectious Diseases,Kunming Yunnan 650041,China)

机构地区：[1]昆明市第三人民医院,云南省传染性疾病临床医学中心,云南昆明650041

出　　处：《昆明医科大学学报》2023年第6期6-13,共8页Journal of Kunming Medical University

基　　金：国家自然科学基金地区资助项目(81960096);云南省科技厅科技计划地方高校联合专项项目(202001BA070001-134);云南省教育厅科学研究基金资助项目(2023J0916);昆明市科技计划重点项目(昆科计字2019-1-N-25318000003253)。

摘　　要：目的建立抗结核药物性肝损伤小鼠模型,探讨抗结核药物性肝损伤机制,提供动物模型依据。方法实验小鼠分为7组,包含对照组,感染结核分枝杆菌(MTB)组,感染MTB后药物灌胃5组:分别灌胃异烟肼(INH)45 mg/(kg·d)、利福平(RIF)90 mg/(kg·d)、乙胺丁醇(EB)135 mg/(kg·d)、吡嗪酰胺(PZA)180 mg/(kg·d)、四联抗结核药物(INH+RIF+EB+PZA),所有给药剂量均按人体剂量与实验动物剂量折算。给药12 h、1~3周后,测定其生化及肝脏指数、病理学指标。结果单次INH、RIF、EB、PZA灌胃及四联抗结核药物灌胃12 h后,RIF组及四联组小鼠血清谷丙转氨酶(ALT)及谷草转氨酶(AST)水平升高(P<0.05)。连续INH、RIF、EB、PZA及四联抗结核药物灌胃1周,INH、RIF、四联组小鼠肝脏血清学指标ALT、AST、TBIL明显升高(P<0.05)、肝脏指数逐步升高,病变范围增大(P<0.05)。连续灌药2~3周后,INH、RIF组、四联组小鼠的肝脏血清学指标ALT、AST、GGT、TBIL持续升高(P<0.05),肝脏指数持续升高(P<0.05)及病变范围逐步扩大(P<0.05)。相关性分析显示INH与RIF具有时间累积效应,用药时间与肝损伤血清学指标、肝脏指数、病变范围明显相关(P<0.05),其余组用药时间与肝损伤指标无明显相关性(P>0.05)。结论四联抗结核药之间有拮抗药物肝脏毒性的趋势,INH及RIF是造成小鼠肝损伤的主导因素,其病理改变以肝细胞损伤为主,且病理指标异常程度早于血清学指标。Objective To establish a mouse model of anti-tuberculous drug-induced liver injury,to explore the mechanism of anti-tuberculous drug induced liver injury,and to provide the basis of animal model.Methods Experimental mice were divided into 7 groups,including control group,group infected with Mycobacterium tuberculosis(MTB),the other 5 groups were given different drugs after infection with MTB,namely isoniazid(INH)45 mg/(kg·d),rifampicin(RIF)90 mg/(kg·d),ethambutol(EB)135 mg/(kg·d),pyrazinamide(PZA)180 mg/(kg·d),tetrad antituberculosis drugs(INH+RIF+EB+PZA),respectively.All doses were converted according to human dose and experimental animal dose.After 12 hours and 1-3 weeks of administration,the biochemical,liver index and pathological indexes were measured.Results After a single intragastric administration of INH,RIF,EB,PZA and tetrad anti-tuberculosis drugs for 12 hours,the levels of serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)in RIF group and tetrad group mice increased(P<0.05).After continuous intragastric administration of INH,RIF,EB,PZA and tetrad antituberculosis drugs for 1 week,the serum indexes of ALT,AST and TBIL in the liver of INH,RIF and tetrad group mice were significantly increased(P<0.05),and the liver index and pathological range were gradually increased and enlarged(P<0.05).After continuous intragastric administration for 2-3 weeks,the serum indexes of liver ALT,AST,GGT and TBIL in INH,RIF and tetrad groups continued to increase(P<0.05),the liver index continued to increase(P<0.05)and the range of lesions expanded(P<0.05).The correlation analysis showed that INH and RIF had a time cumulative effect,and the time of administration was significantly correlated with the serological index,liver index and lesion range of liver injury(P<0.05),while the time of administration in other groups was not significantly correlated with the liver injury index(P>0.05).Conclusion There is a trend of antagonistic liver toxicity among four combination anti-tuberculosis drugs,and INH an

关 键 词：抗结核药物 肝损伤 小鼠模型 指标 分析 

分 类 号：R978.3[医药卫生—药品]