利福平诱导小鼠脂肪肝实验模型的研究

目的：观察利福平( RIF)引起的小鼠肝脏脂肪变及其动态演变过程,为进一步探讨药物性脂肪肝的机制奠定基础。方法将42只成年健康雄性 ICR小鼠随机分为7组(对照组,RIF 8 h、24 h、3 d、1周、2周、4周组),经灌胃给予RIF处理(200 mg/kg),末次给药后禁食6 h处死小鼠,采集血液及肝脏组织。计算肝脏系数；检测血清丙氨酸氨基转移酶( ALT)活性；HE染色观察肝脏组织病理学改变；检测血清中三酰甘油(TG)、胆固醇酯(TCH)、高密度脂蛋白(HDL)、极低密度脂蛋白( VLDL)水平；检测肝脏组织中TG水平；油红O染色检测肝脏组织脂质沉积。结果与对照组比较, RIF处理组小鼠肝脏重量、系数均从24 h开始逐渐升高,4周时达到高峰；与对照组比较,24 h、3 d、1周、2周组ALT水平逐渐升高,4周组ALT水平显著升高。 HE染色显示8、24 h组肝脏组织无明显变化,3 d组可见小的空泡,而从1周开始出现显著增多的大的圆形空泡。8、24 h组血清中TG和VLDL水平较对照组轻度升高,3 d时升高最明显,而1、2、4周组中呈下降趋势,且显著低于对照组。 RIF处理各组血清TCH、HDL水平均较对照组降低。肝脏组织TG含量从8 h开始明显升高,1周时达峰值,之后2、4周组呈下降趋势但仍显著高于对照组。油红O染色结果显示,8、24 h组肝脏组织中可见少量脂质沉积,从3d组开始出现显著增多的大圆形脂滴。结论 RIF能引起小鼠肝脏组织中脂质沉积,且呈明显的时间效应关系。

Mouse model of fatty liver induced by rifampicin

Objective To observe the time-course of rifampicin( RIF)-induced fatty liver in mice in order to lay the foundation for investigating the mechanism of the drug-induced fatty liver. Methods Forty-two healthy male mice were randomly divided into seven groups( control,8 h,24 h,3 d,1 week,2 weeks,4 weeks) , and mice were admin-istered with RIF 200 mg/kg daily by gavage. All mice were sacrificed at 6 h after the last administration to collect serum and liver tissues. All their body weight and liver weight was measured for calculating liver to body weight ra-tio. The levels of alanine aminotranferase( ALT) in serum was measured. Hepatic pathological changes were ob-served by HE staining. The levels of triglyceride ( TG ) , cholesterol ester ( TCH ) , very low density lipoprotein ( VLDL) , high-density lipoprotein( HDL) in serum were measured. Liver tissue was dissected for measuring TG. The lipid accumulation of liver was observed by oil red O staining. Results Compared with control group, liver weight and liver to body weight ratio began to rise gradually 24 h after RIF-treated mice. Compared with mice in control group, the serum levels of ALT slightly increased in 8 h, 24 h, 3 d, 1 week and 2 weeks groups, and sig-nificantly increased in 4 weeks group. HE staining showed 8 h and 24 h after RIF treatment, liver tissue did not see clear change. 3 d group was smaller vacuoles, part of the nucleus to one side, and starting from 1 week liver tissue that was dramatically increasing number of large circular cavity. The levels of TG ,VLDL in the serum were moder-ately elevated in 8 h, 24 h groups,the most obvious was elevated in 3 d group, and begin to decline from 1 week. Serum levels of TCH, HDL in RIF-treated groups were relatively lower than control group. The liver TG levels sig-nificantly increased from 8 h, and peaked in 1 week group, then presented downward trend in 2 weeks and 4 weeks groups but higher than control group. The results of oil red O staining showed that 8 h and 24 h after RIF treat-ment, there was a small amount of lipid deposition in the liver, and large circular lipid drops in liver tissue dramat-ically increased after 3 d. Conclusion Administration of rifampicin causes hepatic steatosis in mice and shows the obvious time-effect relationship.