基于转录组学探讨黄药子诱导胆汁淤积致肝脏毒性的分子机制  

Exploration on the Molecular Mechanism of Dioscoreae Bulbiferae Rhizoma in Inducing Hepatotoxicity through Cholestasis Based on Transcriptomics

作　　者：侯万熙 吴采栋 雷棋博 臧凯宏 HOU Wanxi;WU Caidong;LEI Qibo;ZANG Kaihong(College of Pharmacy,Gansu University of Chinese Medicine,Lanzhou 730000,China;Gansu Key Laboratory of Pharmacology and Toxicology of Traditional Chinese Medicine,Lanzhou 730000,China)

机构地区：[1]甘肃中医药大学药学院,甘肃兰州730000 [2]甘肃省中药药理与毒理学重点实验室,甘肃兰州730000

出　　处：《中国中医药信息杂志》2025年第4期85-91,共7页Chinese Journal of Information on Traditional Chinese Medicine

基　　金：甘肃省自然科学基金(20JR10RA325)。

摘　　要：目的基于转录组学探究黄药子的肝毒性及其分子机制。方法将40只SPF级雄性昆明小鼠随机分为正常对照组和黄药子低、中、高剂量组,连续灌胃黄药子水煎液14 d。检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)含量,HE染色进行肝组织形态观察及病理评分,采用转录组学技术检测肝组织基因表达谱,对差异表达基因进行GO富集分析和KEGG通路富集分析,并通过检测血清碱性磷酸酶(ALP)、肝组织总胆汁酸(TBA)含量及Western blot验证关键靶点。结果与正常对照组比较,黄药子高剂量组小鼠血清ALT、AST含量升高(P<0.05),肝细胞水肿、体积增大,肝血窦扩张,部分区域出现坏死,病理评分升高(P<0.05)。转录组学结果显示,黄药子干预后肝脏差异表达基因主要富集于胆固醇代谢过程、类固醇代谢过程、胆固醇生物合成过程及类固醇生物合成、胆固醇代谢、胆汁分泌、初级胆汁酸生物合成等信号通路。实验验证结果表明,黄药子高剂量组血清ALP及肝组织TBA含量升高(P<0.05),肝组织胆固醇合成相关蛋白3-羟基-3-甲基戊二酰辅酶A合酶1(HMGCS1)、细胞色素P450(CYP)51A1,促进胆固醇转变为胆汁酸蛋白CYP27A1、CYP7A1表达升高(P<0.05,P<0.01),以及促进胆汁酸排泄的阴离子转运体多药耐药蛋白4(MRP4)表达降低(P<0.05)。结论黄药子诱导肝脏毒性与促进胆固醇合成及转化为胆汁酸,抑制胆汁酸排泄有关。Objective To explore the hepatotoxicity of Dioscoreae Bulbiferae Rhizoma and its molecular mechanism using transcriptomics.Methods Totally 40 SPF-grade male Kunming mice were randomly divided into the normal control group and Dioscoreae Bulbiferae Rhizoma low-,medium-and high-dosage groups,and were orally administered with the decoction of Dioscoreae Bulbiferae Rhizoma for 14 days.Serum alanine aminotransferase(ALT)and aspartate aminotransferase(AST)contents were detected,HE staining was used for morphology examination of the liver and scoring,transcriptomic analysis was conducted to detect the gene expression of liver tissue,differentially expressed genes were subjected to GO and KEGG pathway enrichment analysis,serum alkaline phosphatase(ALP)and total bile acid(TBA)content in liver tissue were detected,Western blot was used to validate key targets.Results Compared with the normal control group,Dioscoreae Bulbiferae Rhizoma high-dosage group showed an increase in serum ALT and AST contents(P<0.05),with hepatic cell edema,increased volume,dilated hepatic sinusoids,necrosis in some areas,and elevated pathological score(P<0.05).Transcriptomic analysis revealed that after intervention with Dioscoreae Bulbiferae Rhizoma,differentially expressed genes in liver tissue were mainly enriched in cholesterol metabolism process, steroid metabolism process, cholesterol biosynthesis process, and signaling pathways such as steroid biosynthesis, cholesterol metabolism, bile secretion and primary bile acid biosynthesis. The experimental verification results showed that serum ALP and liver tissue TBA content in Dioscoreae Bulbiferae Rhizoma high-dosage group increased (P<0.05), as well as HMGCS1 and CYP51A1, the expressions of CYP27A1 and CYP7A1, which promoted cholesterol conversion to bile acids in liver tissue increased (P<0.05, P<0.01), while the expression of multidrug resistance protein 4 (MRP4), which promoted bile acid excretion decreased (P<0.05). Conclusion Dioscoreae Bulbiferae Rhizoma inducing liver toxicity is related

关 键 词：黄药子 肝脏毒性 转录组学 胆汁淤积 

分 类 号：R285.5[医药卫生—中药学]