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 and RIF are the main factors causing liver damage in mice.The pathological changes are mainly liver cell damage,and the abnormal degree of pathological indicators is earlier than serological indicators.The use of drugs to protect liver cell lesions in advance may have some clinical significance in preventing liver injury caused by anti-tuberculosis drugs.
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)
出处
《昆明医科大学学报》
CAS
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)。
关键词
抗结核药物
肝损伤
小鼠模型
指标
分析
Anti-tuberculosis drugs
Liver injury
Mouse model
Indicators
Analysis
