吡咯烷二硫代氨基甲酸盐对抗结核药所致肝损伤时高迁移率族蛋白B1表达的影响

Effects of pyrrolidine dithiocarbamateon on the expression of high mobility group box1 of rat liver injury induced by anti- tuberculosis drug

目的研究异烟肼、利福平合用致肝损伤时高迁移率族蛋白B1(HMGB1)与核因子-κB的关系及吡咯烷二硫代氨基甲酸盐(PDTC)对肝损伤的作用。方法 48只雄性SD大鼠随机分为3组:正常组、模型组(异烟肼+利福平,均50mg·kg-1·d-1)、PDTC组(异烟肼+利福平+PDTC,均50 mg·kg-1·d-1)。造模第14,28天,分批处死大鼠,检测大鼠血清胆汁酸(TBA)、总胆红素(TBIL)、直接胆红素(DBIL)、谷丙转氨酶(ALT)、谷草转氨酶(AST)、碱性磷酸酶(ALP)水平,观察大鼠肝病理学变化,免疫组化法检测肝HMGB1蛋白表达,凝胶迁移实验测定核因子-κB活性。结果与正常组相比,模型组大鼠血清TBA、TBIL、DBIL、ALP明显升高(P<0.01),但ALT、AST差异无统计学意义;肝脂肪变性及炎症细胞浸润明显(P<0.01),肝内核因子-κB活性和HMGB1表达水平显著升高。与模型组相比,PDTC组血清TBA、TBIL、DBIL、ALP明显降低(P<0.01);肝病理学变化显著改善,肝内核因子-κB活性和HMGB1表达水平显著降低。结论抑制核因子-κB活性可下调HMGB1的表达;PDTC对异烟肼、利福平合用所致肝损伤的保护作用与其抑制NF-κB/HMGB1途径有关。

Objective To investigate the effect of pyrrolidine dithiocar-bamate （ PDTC） on rat liver injury induced by isoniazid and rifampicinand and study the relationship between nuclear factor -κB （ NF-κB ） and high mobility group box 1 （ HMGB1 ）.Methods Forty -eight male SD rats were randomly divided into normal group , model group （ isoniazid＋rifampicin,both 50 mg· kg-1· d -1）, PDTC group （isoniazid＋rifam-picin ＋PDTC,all 50 mg· kg -1 · d -1 ）.Eight rats in every group were sacrificed respectively on day 14 and 28.The serum levels of total bile acid（TBA）,total bilirubin（TBIL）,direct bilirubin（DBIL）,alanine ami-notransferase （ ALT） ,aspartate aminotransferase （ AST） ,alkaline phospha-tase （ ALP） were measured .The histopathological changes of liver tissues were observed.The expression of HMGBl and NF -κB in livers was respectively detected by immunohistochemistry assay and electrophoresis mobility shift assay.Results Compared with normal group .The serum levels of TBA, TBIL, DBIL, ALP in model group were significantly in-creased （ P〈0.01 ） .The activities of ALT and AST were not significant-ly different （ P ＆gt;0.05 ） . Hepatocyte fatty change , inflammatory cell＆amp;nbsp;infiltration in rat liver of model group were clear （ P〈0.01 ） .The expression of HMGBl and NF -κB activity were ele-vated.Compared with model group , the serum levels of TBA , TBIL, DBIL and ALP were significantly reduced in PDTC group （ P〈0.01 ） .The changes in liver pathology were greatly relieved （ P〈0.01 ） .The expression of HMGBl and NF-κB activity were also reduced .Conclusion Inhibition of NF-κB could down-regulate the expression of HMGB1 in rat liver injury induced by isoniazid and rifampicin.The protective effect of PDTC on the liver injury may be related to the inhibition of NF-κB/HMGB1 pathway.