钝化NF-κB的活化对免疫性肝损伤大鼠CYP2E1的影响  

Effect of blunting NF kappa B activation on CYP2E1 in immunological liver injury rats

作　　者：贾金雪 秦金东[1] 李学峰[1] 康晓琳[1] 高洪波[1] 薛永志[1] 

机构地区：[1]包头医学院药理学教研室,内蒙古包头014060

出　　处：《中国药理学通报》2015年第8期1076-1080,共5页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(No 30760289;81460567);内蒙古自然科学基金资助项目(No 2009MS1104;2014MS0813);内蒙古教育厅资助项目(No NJ03148;NJZY13244);内蒙古卫生厅项目(No 201302099)

摘　　要：目的研究核转录因子-κB(nuclear factor kappa B,NF-κB)在免疫性肝损伤大鼠模型中的作用及对细胞色素P450总含量,亚型2E1(cytochrome P450 2E1,CYP2E1)表达、代谢活力的影响。方法采用尾静脉注射BCG(125 mg·kg-1)14d制备免疫性肝损伤大鼠模型。采用双光束紫外可见分光光度法测定肝匀浆中CYP450总含量,通过肝脏组织HE染色和血清中ALT和AST水平测定观察大鼠肝损伤情况。采用Western blot方法检测大鼠肝组织中CYP2E1蛋白表达;通过HPLC法检测CYP2E1的探针药物氯唑沙宗的血浆药物浓度,从而反映特异性代谢酶CYP2E1的代谢活力。结果大鼠尾静脉注射BCG 14 d后,可引起肝组织炎性细胞浸润,肝重、脾重增加,血清转氨酶ALT及AST水平明显升高,CYP450总含量降低,CYP2E1表达和代谢活力明显降低。采用吡咯烷二硫氨基甲酸(PDTC)钝化NF-κB活化,可抑制CYP450总含量的降低,减缓CYP2E1蛋白表达和代谢活力的下调。结论免疫损伤刺激明显下调CYP2E1,钝化NF-κB活化可明显抑制免疫性肝损伤大鼠肝组织中CYP2E1的下调,NF-κB可能参与CYP2E1下调机制。Aim To determine the function of nuclear faetor-κB （NF-κB）in immunological liver injury of rat model and its effect on CYP2E1 expression, content and metabolic activity. Methods The immunological liver injury rat model was prepared by injection of Ba- cillus Calmette Guerin （ BCG, 125 mg ·kg-l ） for 14 days. The hepatic tissue injury was revealed by hema- toxylin and eosin （HE） method and serum concentra- tion of alanine aminotransferase（ ALT）, aspartate ami- notransferase （AST） respectively. CYP450 total con- tent in hepatic homogenate was determined by speetro- photography. The expression of CYP2E1 protein was detected by Western blot analysis. The enzyme kinetics of CYP2E1 probe drug chlorzoxazone was evaluated by high-performance liquid chromatography （HPLC） as- say. Results The results showed that BCG-pretreat-ment（ 125 mg · kg-1） significantly increased the weight of liver and spleen, serum levels of ALT and AST（P 〈 0.01 ） , and decreased CYP2E1 expression, content and metabolic activity （P 〈 0. 05 ）. Adminis- tration of ammonium pyrrolidine dithiocarbamate （PDTC） （50, 100, 200 mg · kg-1） reversed the a- bove hepatic injury stimulated by BCG in vivo. Moreo- ver, PDTC dose-dependently inhibited the down regu- lation of CYP2E1 （P 〈 0.05 ）. Conclusion Passiva- tion of NF-κB can inhibit the down regulation of CYP2E1 in liver tissue of immunological liver injury rats; NF-κB may be involved in CYP2E1 down-regula- tion.

关 键 词：肝损伤 核转录因子-ΚB 吡咯烷二硫氨基甲酸 细胞色素P4502E1 大鼠 细胞色素P450 卡介苗 

分 类 号：R-332[医药卫生] R322.47