泽泻水醇提取物改善千里光碱致小鼠急性肝损伤的作用与机制研究  

The protective effects and mechanism of Alismatis Rhizoma extracts against senecionine-induced acute liver injury in mice

作　　者：姜凯元 叶铉玲 熊芬 张祎 杨莉[1,2] 熊爱珍 王峥涛[1,2] JIANG Kai-yuan;YE Xuan-ling;XIONG Fen;ZHANG Yi;YANG Li;XIONG Ai-zhen;WANG Zheng-tao(The MOE Key Laboratory for Standardization of Chinese Medicines and the SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines,Institute of Chinese Materia Medica,Shanghai University of Traditional Chinese Medicine,Shanghai 201203,China;Shanghai R&D Center for Standardization of Traditional Chinese Medicines,Shanghai 201203,China)

机构地区：[1]上海中医药大学中药研究所,中药标准化教育部重点实验室暨国家中医药管理局中药新资源与质量评价重点实验室,上海201203 [2]上海中药标准化研究中心,上海201203

出　　处：《药学学报》2021年第3期823-830,共8页Acta Pharmaceutica Sinica

基　　金：上海市自然科学基金资助项目(20ZR1473300);上海市进一步加快中医药事业发展三年行动计划(2018年-2020年,ZY(2018-2020)-CCCX-5002);上海市人才发展资金;上海中医药大学“杏林学者”计划;上海中医药大学“研究生创新培养专项”科研项目(Y2021089)。

摘　　要：近年来,含吡咯里西啶生物碱(pyrrolizidine alkaloid,PA)的中草药所致药源性肝损伤引起了国内外的广泛关注,但缺乏有效的临床治疗药物。因此,本文研究中药泽泻对代表性PA千里光碱(senecionine,SEN)所致急性肝损伤的改善作用,并初步探讨其潜在的药理作用机制。实验方案经上海中医药大学实验动物福利与伦理委员会审查,符合实验动物福利与伦理相关规范。小鼠单次灌胃SEN(50 mg·kg^(-1))造成急性肝损伤模型,并设泽泻水提物(18 g·kg^(-1))保护组、泽泻醇提物(18 g·kg^(-1))保护组和空白对照组。结果表明,泽泻对SEN致小鼠急性肝损伤有明显的保护作用:泽泻提取物可显著降低急性肝损伤小鼠血清谷丙转氨酶、谷草转氨酶活性及总胆汁酸水平,炎性细胞浸润、肝窦淤血、肝组织坏死等病理变化均有所缓解,且醇提物药效优于水提物。进一步测定血清中主要胆汁酸的含量和肝脏胆汁酸代谢相关因子的mRNA和蛋白表达,发现泽泻可调控胆汁外排转运体和肝脏代谢酶的表达,维护胆汁酸代谢平衡,修复受损的肝细胞。本研究为临床上应用泽泻防治PA致肝损伤提供了理论依据。Drug-induced liver injury and herbal preparations containing pyrrolizidine alkaloid(PA)have gained global attention.The purpose of this research was to investigate the effects and mechanisms of Alismatis Rhizoma,a traditional Chinese medicine,to protect against acute liver injury in mice induced by senecionine(SEN),a representative toxic PA compound.All experiments were approved by the Animal Research Committee of Shanghai University of Traditional Chinese Medicine.Animal welfare and the animal experimental protocols were strictly consistent with related ethics regulations of Shanghai University of Traditional Chinese Medicine.Acute liver injury was induced by a single intragastric administration of SEN(50 mg·kg^(-1)).Mice in the protection groups received intragastric administration of Alismatis Rhizoma water extract(WE,18 g·kg^(-1) per day)or ethanol extract(EE,18 g·kg^(-1) per day)5 days before SEN treatment.The results show that Alismatis Rhizoma extracts can significantly attenuate acute liver injury in mice.Mice in the protection groups showed decreased serum activities of alanine aminotransferase and aspartate aminotransferase,as well as decreased total bile acids.In addition,the infiltration of inflammatory cells,sinusoidal hemorrhage,and hepatic necrosis in SEN-treatment mice was clearly attenuated in the protection groups.Interestingly,EE showed a better effect than WE.The content of principal bile acids in serum and the mRNA and protein expression of key factors related to bile acid metabolism were also measured.Alismatis Rhizoma up-regulated the bile acid transporters and drug metabolism enzymes,consistent with the observed bile acid homeostasis and alleviation of SEN-induced injury to hepatocytes.The present study points to the possibility of utilizing Alismatis Rhizoma for protection against liver injury caused by drugs and preparations containing PA.

关 键 词：泽泻 胆汁酸 吡咯里西啶生物碱 千里光碱 药源性肝损伤 

分 类 号：R917[医药卫生—药物分析学]