甘草次酸调控铁死亡缓解舒尼替尼肝损伤的机制研究  

Glycyrrhetinic acid alleviates sunitinib-induced liver injury via regulating ferroptosis and related mechanism

作　　者：曹蓉 刘灵 郭林 夏爽 罗欢 颜苗[2] 江志超[1,3] CAO Rong;LIU Ling;GUO Lin;XIA Shuang;LUO Huan;YAN Miao;JIANG Zhi-chao(Hunan University of Chinese Medicine,Changsha 410208;Department of Pharmacy,the Second Xiangya Hospital of Central South University,Changsha 410011;The First Affiliated Hospital of Hunan Chinese Medicine College,Zhuzhou Hunan 410016)

机构地区：[1]湖南中医药大学,长沙410208 [2]中南大学湘雅二医院药学部,长沙410011 [3]湖南中医药高等专科学校附属第一医院,湖南株洲410016

出　　处：《中南药学》2024年第8期1993-1998,共6页Central South Pharmacy

基　　金：湖南省自然科学基金杰出青年基金(No.2022JJ10097);湖南省自然科学基金(No.2023JJ60351);湖南省教育厅优秀青年基金(No.21B0014);中国药学会医院药学专业委员会人才专项资助项目(No.CPA-Z05-ZC-2021-003);湖南省中医药管理局(No.A2023032)。

摘　　要：目的探讨甘草次酸(GA)对舒尼替尼诱导的肝损伤的保护作用及机制。方法首先提取美国FDA药物不良反应数据库(FAERS)中使用舒尼替尼与其他治疗转移性肾细胞癌和胃肠道间质瘤的药物的肝脏不良事件(AEs)数据,采用贝叶斯法计算药物与不良反应的信号关联强度,对比舒尼替尼与其他抗肿瘤药物的肝毒性风险。其次在动物水平上,将小鼠随机分为正常对照组、舒尼替尼组(120 mg·kg^(-1))、舒尼替尼+GA低剂量组(10 mg·kg^(-1))、舒尼替尼+GA高剂量组(20 mg·kg^(-1)),每组5只,各组小鼠每日灌胃给药,连续2周。给药结束后检测小鼠血清谷丙转氨酶(ALT)、谷草转氨酶(AST)水平;苏木素伊红(HE)染色观察肝组织病理变化;试剂盒测定肝组织脂质过氧化物(LPO)、丙二醛(MDA)及铁(Fe)含量;Western blot分别检测核因子E2相关因子2(Nrf2)、溶质载体家族7成员11(SLC7A11)、血红素氧合酶(HO-1)、谷胱甘肽过氧化物酶4(GPX4)的蛋白表达情况。结果FAERS数据库信号挖掘分析发现舒尼替尼相比于其他治疗转移性肾细胞癌和胃肠道间质瘤的药物,与肝脏AEs存在的信号关联性更为显著,尤其与黄疸、高胆红血素症、AST升高、肝衰竭紧密相关。在动物实验结果中,与正常对照组相比,舒尼替尼组血清ALT、AST水平显著升高;HE染色结果显示明显的肝细胞肝索排列紊乱、空泡样变及炎性细胞浸润;LPO、MDA和Fe含量明显升高;Nrf2、SLC7A11、HO-1、GPX4蛋白均表达降低。与GA联合后,ALT、AST水平明显降低;肝组织病理损伤程度得到一定的恢复;LPO、MDA和Fe水平降低;Nrf2、SLC7A11、HO-1及GPX4蛋白表达增加。结论GA可有效缓解舒尼替尼所致的肝损伤,其作用机制可能与抑制铁死亡有关。Objective To determine the protective effect and of glycyrrhetinic acid(GA)on sunitinibinduced liver injury related mechanism.Methods Firstly,adverse event(AE)data of sunitinib and other drugs used for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors were collected from the US Food and Drug Administration Adverse Event Reporting System(FAERS)database.The signal association strength between the drugs and AEs was calculated with Bayesian method,and the hepatotoxicity risk of sunitinib was compared with that of other antitumor drugs.At the animal level,mice were randomly divided into a normal control group,a sunitinib group(120 mg·kg^(-1)),a sunitinib plus low-dose GA group(10 mg·kg^(-1)),and a sunitinib plus high-dose GA group(20 mg·kg^(-1)),with 5 mice in each group.The mice in each group were orally administered daily for 2 weeks.After the treatment,the levels of serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)were measured.Hematoxylin-eosin(HE)staining was used to observe the pathological changes in the liver tissues.The levels of lipid peroxides(LPO),malondialdehyde(MDA),and iron(Fe)in the liver tissues were determined by assay kits.Western blot was used to detect the protein expression of nuclear factor E2-related factor 2(Nrf2),solute carrier family 7 member 11(SLC7A11),heme oxygenase-1(HO-1),and glutathione peroxidase 4(GPX4).Results The signal mining of the FAERS database showed that sunitinib had a more significant association with the liver AEs than did other drugs in the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors,especially for patients with jaundice,high bilirubin levels,AST elevation,and liver failure.In the animal experiment,compared with the normal control group,the serum ALT and AST levels in the sunitinib group significantly increased.HE staining showed obvious disorder in the liver cell cords,vacuolar degeneration,and inflammatory cell infiltration.The levels of LPO,MDA,and Fe were significantly incr

关 键 词：甘草次酸 肝损伤 舒尼替尼 铁死亡 

分 类 号：R285[医药卫生—中药学]