马兜铃酸Ⅰ致C57BL/6和C3H/He小鼠急性毒性研究  

Short-term toxicity of aristolochic acids I in C57BL/6 and C3H/He mice

作　　者：霍桂桃[1] 秦超 王超[1] 林志[1] 屈哲[1] 李双星 杨艳伟[1] 张頔[1] 文海若 HUO Guitao;QIN Chao;WANG Chao;LIN Zhi;QU Zhe;LI Shuangxing;YANG Yanwei;ZHANG Di;WEN Hairuo(Key Laboratory of Beijing for Safety Evaluation of Drugs,National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control,Beijing 100176,China)

机构地区：[1]中国食品药品检定研究院国家药物安全评价监测中心,药物非临床安全评价研究北京市重点实验室,北京100176

出　　处：《药物评价研究》2024年第8期1827-1837,共11页Drug Evaluation Research

基　　金：国家自然科学基金资助项目(81503347);药品监管科学全国重点实验室课题(2023SKLDRS0128)。

摘　　要：目的拟通过比较不同品系小鼠对马兜铃酸I(AAI)的耐受性及急性毒性反应,以期为研究AAⅠ提供借鉴和指导。方法采用ig给药方式,单次给予C57BL/6和C3H/He小鼠AAⅠ(5.0、9.3、17.1、31.7、58.6、108.4、200.5 mg·kg^(-1)),每种品系小鼠均设置1个溶媒对照组,并于给药后进行一般症状观察及体质量测定。试验结束进行剖检、脏器称质量、血清生化指标检测及病理学检查。结果单次给予一定剂量AAⅠ可引起2种品系小鼠出现体质量下降、消瘦、弓背及活动减少,甚至死亡,并且C57BL/6小鼠出现上述改变的AAⅠ剂量低于C3H/He小鼠。C57BL/6小鼠的AAⅠ半数致死量(LD50)为38.07 mg·kg^(-1),C3H/He小鼠的AAⅠLD50为59.92 mg·kg^(-1)。C57BL/6小鼠AAⅠ最大耐受剂量(MTD)为17.1 mg·kg^(-1),C3H/He小鼠的AAⅠMTD为31.7 mg·kg^(-1)。给予一定剂量的AAI后,C57BL/6小鼠各项血清生化指标未见改变,而C3H/He小鼠血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、肌酐(CRE)水平升高。AAI可引起C57BL/6、C3H/He小鼠多个脏器出现急性损伤,如胸腺、脾脏、肾脏、肝脏及前胃,并且引起C3H/He小鼠上述组织器官出现组织病理学改变的AAⅠ剂量均低于C57BL/6小鼠。结论通过对不同剂量AAⅠ所引起C57BL/6和C3H/He小鼠整体毒性、血清生化指标、动物死亡原因以及组织病理学改变分析,认为C3H/He小鼠对AAⅠ的急性毒性比C57BL/6小鼠更加敏感。既验证了AAⅠ致C57BL/6和C3H/He小鼠的急性毒性特点和作用的靶器官,也为研究不同品系小鼠对AAⅠ急性毒性的敏感性和耐受性提供了数据支持。Objective To compared the tolerance and toxicity of different strains of mice to aristolochic acid I(AAI)to provide a reference and guidance for the study of AAI.Methods C57BL/6 and C3H/He mice were treated with AAⅠby oral gavage.Each strain of mice was assigned one vehicle control and seven AAI dose(5.0,9.3,17.1,31.7,58.6,108.4,and 200.5 mg·kg^(-1))groups,and clinical symptom observation and weight measurement were performed after dosing.At the end of the experiment,necropsy,organ weighing,serum biochemical index detection,and pathological examination were performed.Results A single administration of a certain dose of AAI caused weight loss,emaciated,arched back,reduced activity,and even death in both strains of mice,and the dosage of AAⅠin C57BL/6 mice with the above changes was lower than that in C3H/He mice.The AAⅠmedian lethal dose(LD50)of C57BL/6 mice was 38.07 mg·kg^(-1),and that of C3H/He mice was 59.92 mg·kg^(-1).The maximum tolerated dose(MTD)of AAI in C57BL/6 mice was 17.1 mg·kg^(-1),and that in C3H/He mice was 31.7 mg·kg^(-1).AAI did not induce serum biochemical changes in C57BL/6 mice,while increased levels of ALT,AST,and CRE were found in C3H/He mice.AAI can cause acute injury to multiple organs in C57BL/6 and C3H/He mice,such as the thymus,spleen,kidneys,liver,and forestomach.And the dose of AAⅠcausing histopathological changes in the the above-mentioned tissues and organs of C3H/He mice was lower than that of C57BL/6 mice.Conclusion By analyzing the overall toxicity,serum biochemical indicators,causes of animal death,and histopathological changes caused by different doses of AAⅠin C57BL/6 and C3H/He mice,it was concluded that C3H/He mice were more sensitive to acute toxicity of AAⅠthan C57BL/6 mice.This study not only verified the acute toxicity characteristics and target organs of AAⅠon C57BL/6 and C3H/He mice,but also provided rich data support for comparing the sensitivity and tolerance of different strains of mice to AAⅠacute toxicity,and provided detailed reference data f

关 键 词：马兜铃酸I C57BL/6小鼠 C3H/He小鼠 急性毒性 肾毒性 

分 类 号：R965.3[医药卫生—药理学]