丙酮酸乙酯对利福平致小鼠肝损伤的保护作用

Protective effects of ethyl pyruvate on liver injury induced by rifampicin in mice

目的探讨丙酮酸乙酯(EP)对利福平致小鼠肝损伤的保护作用及其可能机制。方法 24只C57BL/6小鼠随机分成3组:正常对照组、模型组(利福平,200 mg·kg^(-1)·d^(-1))和EP组(利福平200 mg·kg^(-1)·d^(-1)+丙酮酸乙酯40 mg·kg^(-1)·d^(-1)),每组8只。造模后第7天处死小鼠,检测小鼠血清谷丙转氨酶(ALT)、总胆红素(TBIL)、直接胆红素(DBIL)、碱性磷酸酶(ALP),观察小鼠肝脏病理学变化,检测小鼠肝组织总胆汁酸(TBA)、丙二醛(MDA)的含量、超氧化物歧化酶(SOD)活性、高迁移率族蛋白B1(HMGB1)及乙酰化的HMGB1(AC-HMGB1)蛋白的表达情况。结果与正常对照组相比,模型组小鼠血清TBIL、DBIL、ALP、ALT水平升高(P<0.05);肝细胞空泡变性、脂肪变性明显,部分肝细胞可见嗜酸性变、核溶解或固缩;肝组织TBA、MDA的含量提高(P<0.05),SOD减少(P<0.05),HMGB1及AC-HMGB1表达增多(P<0.05),HMGB1胞浆表达为主。与模型组相比,EP组小鼠血清TBIL、DBIL、ALP、ALT水平降低(P<0.05);肝组织病理学变化改善;肝组织TBA、MDA的含量降低(P<0.05),SOD增多(P<0.05),HMGB1及AC-HMGB1的表达水平降低(P<0.05),HMGB1以胞核表达为主。结论丙酮酸乙酯能够减轻利福平所致的小鼠肝损伤,其机制可能与丙酮酸乙酯抗氧化,下调肝组织HMGB1及AC-HMGB1的表达和调节HMGB1的分布有关。

Objective To investigate the protective action of ethyl pyruvate on liver injury induced by rifampicin in mice and its possible mechanism.Methods Twenty-four male C57BL/6 mice were randomly divided into normal group,model group(rifampicin,200 mg·kg-1·d-1)and ethyl pyruvate group(rifampicin,200 mg·kg-1·d-1+ethyl pyruvate,40 mg·kg-1·d-1).Each group consisted of eight animals.The mice were sacrificed on day 7.The serum levels of alanine aminotransferase(ALT),total bilirubin(TBIL),direct bilirubin(DBIL)and alkaline phosphatase(ALP)were measured.The histopathological changes of liver tissues were observed.The liver tissue was dissected for measuring TBA,MDA,SOD and acetylated-high mobility group box-1.The expression of high mobility group box-1 in liver was detected by immunohistochemistry.Results Compared with normal group,the serum levels of TBIL,DBIL,ALP and ALT in model group significantly increased(P<0.05).Obvious vacuolar degeneration and fatty changes of hepatocyte and eosinophi changes,nucleus dissolution and condensation of a few hepatocyte in mice of model group were observed.The expressions of HMGB1 and AC-HMGB1 were elevated(P<0.05),and HMGB1 was mostly located in hepatocyte cytoplasm.Compared with model group,the serum levels of TBIL,DBIL,ALP and ALT were significantly reduced in EP group(P<0.05).The changes in liver pathology were greatly relieved.The levels of TBA and MDA in liver tissue were also significantly reduced(P<0.05),but the level of SOD was significantly elevated(P<0.05).The expressions of HMGB1 and AC-HMGB1 were also reduced(P<0.05),and HMGB1 was mostly located in hepatocyte nucleus.Conclusion Rifampicin may cause severe hepatic damage,and EP could reduce the degree of liver injury.The mechanism may be that EP not only has antioxidant activity,but also can down-regulate the expression of HMGB1 and AC-HMGB1 in liver tissue and regulate the distribution of HMGB1.