利福平致大鼠胆汁淤积性肝损伤适应性现象的研究

摘要

利福平广泛用于抗结核治疗,是引起药物性肝损伤的主要原因之一.目的:探讨利福平致大鼠胆汁淤积性肝损伤的特征及其动态变化.方法:32只Wistar大鼠随机分成正常对照组和利福平模型组,采用利福平灌胃制备胆汁淤积性肝损伤大鼠模型.动态监测造模第0、7、14、21、28、35、42、49 d大鼠血清ALT、AST、ALP活性以及TBIL、DBIL含量变化.造模第14、49 d分批处死大鼠,观察大鼠肝组织超微结构改变,检测肝匀浆TBA、MDA含量和SOD、GSH-Px活性.结果:利福平模型组血清ALT、AST、ALP活性和TBIL、DBIL含量于给药后升高,第7～21 d达高峰,显著高于正常对照组(P＜0.05),之后呈现缓慢下降趋势,第49 d ALT、AST活性和DBIL含量与正常对照组相比差异无统计学意义(P＞0.05).利福平模型组肝组织电镜下可见线粒体肿胀、内质网断裂、毛细胆管扩张以及胆汁淤积.造模第14、49 d利福平模型组TBA、MDA含量较正常对照组显著升高(P＜0.01,P＜0.05),第49 dTBA含量较第14 d显著降低(P＜0.05),MDA含量较第14 d有所降低,但差异无统计学意义(P＞0.05).第14 d利福平模型组SOD、GSH-Px活性较正常对照组相比显著降低(P＜0.01,P＜0.05),第49 d利福平模型组SOD、GSH-Px活性较第14 d相比有所降低,但差异无统计学意义(P＞0.05).结论:利福平可导致以胆汁淤积为主的肝损伤,并存在肝损伤适应性现象.%Background; Rifampicin is widely used for anti-tuberculosis treatment, however, it is one of the main cause for hepatic injury. Aims: To investigate characteristics of rifampicin induced cholestatic hepatic injury and its time course in rats. Methods; A total of 32 Wistar rats were randomly divided into normal control group and rifampicin model group. The cholestatic hepatic injury model in rats was established by rifampicin lavage. The activities of ALT, AST, ALP as well as the contents of TBIL and DBIL were detected on day 0, 7, 14, 21, 28, 35, 42, 49. The rats were sacrificed on day 14 and 49, and ultrastructure of hepatic tissue was observed. The contents of TBA and MDA as well as the activities of SOD and GSH-Px in hepatic homogenate were detected. Results; The activities of ALT, AST and ALP as well as the contents of TBIL and DBIL in rifampicin model group were increased after induction of hepatic injury (P < 0. 05 ) , reached the highest level on day 7 to 21 and then decreased slowly, the activities of ALT and AST as well as the content of DBIL between rifampicin model group and normal control group were not significantly different on day 49 (P > 0. 05). Hepatic tissue ultrastructure showed swelling of mitochondria, interruption of endoplasmic reticulum, dilatation of cholangiole and cholestasis in rifampicin model group. The contents of TBA and MDA in rifampicin model group were significantly higher than those in normal control group on day 14 and 49 after induction of hepatic injury (P < 0.01, P < 0.05), the content of TBA on day 49 was significantly lower than that on day 14 ( P < 0.05 ) , and the content of MDA on day 49 was slightly lower than that on day 14 but the difference was not statistically significant ( P > 0.05 ). The activities of SOD and GSH-Px in rifampicin model group were significantly lower than those in normal control group on day 14(P <0.01 ,P <0. 05) , and the activities of SOD and GSH-Px on day 49 were lower than those on day 14 but the difference was not statistically significant ( P > 0. 05). Conclusions; Rifampicin can cause cholestatic hepatic injury, which has an adaptation phenomenon.