基于肝药酶P450动态变化的柴胡总皂苷小鼠肝毒性剂量-时间-毒性关系研究

Research on Mechanism of Hepatotoxicity Caused by Extracts of Saikosaponins in Mice

目的:研究单次给予柴胡总皂苷致小鼠肝毒性损伤的程度及其机制。方法:按小鼠急性肝毒性剂量-时间-毒性(量-时-毒)关系研究方法进行。时-毒关系研究:小鼠ig一定剂量(36.075 g·kg-1)的柴胡总皂苷提取物,分别于给药后不同时间点检测血清细胞色素P450(CYP450)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)水平,解剖,取肝脏,光学显微镜下观察肝组织形态变化;量-毒关系研究:给小鼠ig不同剂量(36.075,21.650,12.975,7.925,4.675 g·kg-1)的柴胡总皂苷提取物,于给药后2 h按时-毒实验方法进行相应处理。结果:对柴胡总皂苷致小鼠肝毒性时-毒关系研究显示:小鼠单次ig柴胡总皂苷提取物后1 h血清CYP450,ALT,AST水平开始升高,与0 h组比较均有极显著性差异,并分别于药后8,2,2 h达到峰值,之后逐渐恢复。对柴胡总皂苷致小鼠肝毒性量-毒关系研究显示:小鼠单次ig不同剂量的柴胡总皂苷提取物后2 h血清CYP450,ALT,AST水平均有不同程度升高,且呈现一定的剂量相关性。光学显微镜下观察,柴胡总皂苷提取物组小鼠肝组织出现不同程度的肝细胞水肿和脂肪变性,其中高剂量组可出现片状坏死、小叶结构不清等病变。结论:柴胡总皂苷的肝毒作用机制可表现在影响肝脏对药物的代谢能力方面。

Objective： To observe the degree and mechanism of the hepatotoxicity induced by extract of saikosaponin in mice. Method： The time-toxicity relationship in mice were observed by giving the dosage of 36. 075 g .kg-1 of extract of total saikosaponins and the changes of cytochrome P450 （CYP450） and alenine transaminase （ALT）, aspartase aminotransferase （AST） were tested at different time points after being administered, and the morphological changes of hepatic tissue were observed by light microscope. The dosage- toxicit relationship in mice wereobserved by giving different dosages （36. 075 . 21. 650, 12. 975, 7. 925, 4. 675 g .kg-1 respectively） of extract of total saikosaponins and the corresponding treatment was performed 2 hours after administration in accordance with the method of iime-toxicit relationship study. Result： The time-toxicity relationship study indicated that the level of CYPd50 and ALT, AST in serum began to increase at 1 h after administration, and showed obvious differences compared with the control group, then it reached a peak level at 8, 2 h and 2 h respectively. The dose-toxicity relationship study indicated that, compared with the control group, the level of CYP450 and ALT, AST in serum increased to different degrees at 2 h after admir[istration, which showed a correlation with the dosage. Conclusion： The hepatotoxicity induced by the extract of saikosaponins is related to drug metabolism ability of the liver.