【摘要】 目的:探讨熊果酸对酮康唑肝毒作用的影响及机制。方法:酮康唑100 mg/kg灌胃21 d,制作小鼠慢性肝损伤模型。熊果酸高低剂量和双环醇给药7 d,测血清ALT、AST、ALP、TBil值、血糖水平及肝糖原含量;观察肝组织病理变化;单细胞凝胶电泳观察肝细胞核DNA完整性;流式细胞术测定肝细胞凋亡率和细胞周期。结果:酮康唑组sALT、sAST、ALP和肝指数均明显高于生理盐水对照组(P<0.01),TBil水平无明显改变,肝细胞广泛变性坏死,肝组织内脂质大量堆积,彗星电泳显示肝细胞核DNA片段化明显,流式细胞仪检测结果表明肝细胞凋亡坏死率明显高于空白对照组(P<0.05),肝细胞G2/M期停滞。熊果酸400 mg/(kg.d)可明显降低酮康唑所致sALT、sAST、ALP水平和肝指数的上升,使脂质沉积减少,肝细胞坏死程度降低,彗星样肝细胞出现减少,彗星尾长缩短,肝细胞凋亡坏死率降低,肝细胞G2/M期停滞明显改善。结论:熊果酸能减轻酮康唑引起小鼠肝毒作用。其机制可能与减少脂质堆积,保护肝细胞DNA完整或有助于DNA修复有关。更多还原

【Abstract】 Objective :To investigate the effect of Ursolic acid(UA) on Ketoconazole(KET)-inducedhepatotoxicity and the possible mechanisms involved in this protection effect.Methods :Hepato-toxicity was induced in mice by intragastric administration of KET [100 mg/(kg.d)] for 21days.UA[100 and 400 mg/(kg.d),respectively] was intragastric administered for seven daysafter KETadministered for 14 days.The blood and liver samples were collected for testing thelevel of sALT,sAST,ALP,TBil,BGlu,hepatic glycogen and liver index.The pathologicalchanges were observed.Single cell gel electrophoresis was used to detect the integrity of DNA.Apoptosis and cell cycle was evaluated byflowcytometry.Results :Treat ment of mice with Keto-conazole resultedin a significant increase of thelevel of sALT,sAST,ALP,BGlu andliverindexrespectively(allP<0.01),and decreases of hepatic glycogen content and TBil level were not sig-nificant.Multiplicity hepatic cells necrosis,lipid accumulatedinliver and DNAfragmentation ofhepatic cells nucleus were observed.The apoptosis rate of hepatic cells increased(P<0.05),andcell cycle was blockedin G2/ M.UAat 400 mg/(kg.d) reversed the changes of sALT,sAST,ALP,BGlu,liver index and hepatic glycogen,rebounded pathological change,and decreased theapoptosis rate of hepatic cells and the percentage of comet-like hepatic cells.Conclusion:Ursolicacid can resist hepatotoxicity induced by Ketoconazole.The possible mechanisms maybe relatedto maintainingintegrity of DNAof hepatic cell nucleus,promoting DNArepair or decreasinglipidaccumulationinliver.更多还原