水溶性联苯类化合物WLP-S-14在实验性肝损伤模型中的保护作用

摘要

Objective To assess the hepatoprotective effect of a water solubility derivative of biphenyl by three acute liver failure models. Methods Two mice models of acute liver failure were established by injection with carbon tetrachlo-ride (CCl4) or concanavalin A(Con A) respectively. Mice were intraperitoneally injected with two doses of WLP-S-14 (100 200 mg·kg-1) before administration of CCl4 and Con A. Serum alanine aminotransferase(ALT) and glutamate oxaloacetate transaminase (AST) were detected by automatic chemistry analyzer (TBA-40FR). At the same time, oxaliplatin and 5-fluorouracil were injected to induce liver failure in Lewis-bearing mice. WLP-S-14(100,200mg·kg-1) was pretreated 2hr before the injection of oxaliplatin/5-fluorouracil. The activities of ALT and AST in serum were measured by automatic chemistry analyzer and liver histopathological changes were examined by H.E. and light microscopy. Results In CCl4-induced liver damage mice, WLP-S-14 100mg·kg-1 significantly reduced the elevated serum AST and ALT levels induced by CCl4. WLP-S-14 200mg·kg-1 also markedly decreased sersum ALT, but there was no significantly statistical significance on the decrease of AST when compared with the model group. In Con A-induced immunologic liver injury mice, pretreation of WLP-S-14 (100 200mg·kg-1) both markedly decreased the elevated ALT and AST induced by Con A. WLP-S-14 (100, 200mg·kg-1) also showed a significant protection in oxaliplatin/5-fluorouracil-induced liver damage mice, as evidenced by the improvement of histopathological injury and the decrease of elevated serum aminotransferases. There was no decline to tumor inhibition rate produced by oxaliplatin/5-fluo-rouracilwhenco-administration WLP-S-14 100mg·kg-1. Conclusion WLP-S-14 showed potent protective activities against CCl4, Con A or oxaliplatin/5-fluorouracil-induced liver damage. It is worth exploring for future study.%目的：考察新型水溶性联苯类化合物WLP-S-14在3种实验性小鼠肝损伤模型中的保护作用。方法建立四氯化碳（CCl4）、刀豆蛋白A（Con A）诱发的小鼠急性肝损伤模型，WLP-S-14（100、200 mg·kg-1）在给予肝毒性物质前2天连续3次腹腔注射给药，全自动生化分析仪检测血清ALT及AST水平。建立奥沙利铂（Oxaliplatin，L-OHP）联合5-氟尿嘧啶（5-Fluorouracil，5-FU）诱发的荷瘤小鼠肝损伤模型，WLP-S-14（100、200 mg·kg-1）腹腔注射给药，连续7天，H.E.染色观察肝脏病理状态，全自动生化分析仪检测血清ALT及AST水平，同时计算抑瘤率并观察动物死亡情况。结果在CCl4诱导的急性中毒性肝损伤模型，WLP-S-14100 mg·kg-1对CCl4引起的小鼠血清ALT、AST的升高均有显著降低作用，WLP-S-14200mg·kg-1对ALT的降低作用显著，对AST仅有降低的趋势但无统计学意义；在Con A诱导的急性免疫性肝损伤模型中，WLP-S-14100、200mg·kg-1可显著降低Con A引起的血清ALT、AST升高，200mg·kg-1活性略优于同剂量的双环醇组；在L-OHP联合5-FU诱发的荷瘤小鼠药物性肝损伤模型，WLP-S-14100、200mg·kg-1对L-OHP/5-FU引起的荷Lewis肺癌小鼠肝脏损伤表现显著改善作用，能降低血清ALT、AST水平，改善肝脏病理状态。WLP-S-14100 mg·kg-1对L-OHP/5-FU的抑瘤率无降低作用，且能改善小鼠因L-OHP/5-FU而引起的体重下降状况。结论新型水溶性联苯类化合物WLP-S-14对多种原因引起的小鼠肝损伤均显示显著的保护作用，值得进一步开发研究。