Timosaponin A3 induces hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters
文献类型：期刊论文
| 作者 | Wu, Zhi-tao1; Qi, Xin-ming1 ; Sheng, Jing-jing3; Ma, Lei-lei1; Ni, Xuan1; Ren, Jin1; Huang, Cheng-gang2; Pan, Guo-yu1
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2014-09 |
| 卷号 | 35期号:9页码:1188-1198 |
| 关键词 | timosaponin A3 hepatotoxicity cholestasis bile acid transporter Cyp7a1 ROS N-acetyl-L-cysteine mangiferin |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2014.65 |
| 文献子类 | Article |
| 英文摘要 | Aim: To investigate the mechanisms underlying the hepatotoxicity of timosaponin A3 (TA3), a steroidal saponin from Anemarrhena asphodeloides, in rats. Methods: Male SD rats were administered TA3 (100 m.kg(-1)d(-1), po) for 14 d, and the blood and bile samples were collected after the final administration. The viability of a sandwich configuration of cultured rat hepatocytes (SCRHs) was assessed using WST-1. Accumulation and biliary excretion index (BEI) of d8-TCA in SCRHs were determined with LC-MS/MS. RT-PCR and Western blot were used to analyze the expression of relevant genes and proteins. ROS and ATP levels, and mitochondrial membrane potential (MMP) were measured. F-actin cytoskeletal integrity was assessed under confocal microscopy. Results: TA3 administration in rats significantly elevated the total bile acid in serum, and decreased bile acid (BA) component concentrations in bile. TA3 inhibited the viability of the SCRHs with an IC50 value of 15.21 +/- 1.73 mu mol/L. Treatment of the SCRHs with TA3 (1-10 mu mol/L) for 2 and 24 h dose-dependently decreased the accumulation and BEI of d8-TCA. The TA3 treatment dose-dependently decreased the expression of BA transporters Ntcp, Bsep and Mrp2, and BA biosynthesis related Cyp7a1 in hepatocytes. Furthermore, the TA3 treatment dose-dependently increased ROS generation and HO-1 expression, decreased the ATP level and MMP, and disrupted F-actin in the SCRHs. NAC (5 mmol/L) significantly ameliorated TA3-induced effects in the SCRHs, whereas mangiferin (10-200 mu g/mL) almost blocked TA3-induced ROS generation. Conclusion: TA3 triggers liver injury through inducing ROS generation and suppressing the expression of BA transporters. Mangiferin, an active component in Anemarrhena, may protect hepatocytes from TA3-induced hepatotoxicity. |
| WOS关键词 | SANDWICH-CULTURED HEPATOCYTES ; DRUG-INDUCED HEPATOTOXICITY ; INDUCED LIVER-INJURY ; SALT EXPORT PUMP ; ANEMARRHENA-ASPHODELOIDES ; ALPHA-NAPHTHYLISOTHIOCYANATE ; HEPATOBILIARY TRANSPORT ; INDUCED CHOLESTASIS ; BILIARY-EXCRETION ; MECHANISM |
| 资助项目 | National Natural Science Foundation of China[81302836] ; National Natural Science Foundation of China[81030065] ; National Natural Science Foundation of China[81274055] ; Hundred Talents Program of the Chinese Academy of Sciences[00000000] ; Major National Science and Technology Programs[2012ZX09301001-006] ; Major National Science and Technology Programs[2012ZX09302003] ; National High Technology Research and Development Program of China[2013AA032202] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5230248 |
| WOS记录号 | WOS:000341225700010 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276924]  |
| 专题 | 上海中药现代化研究中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 药物安全性评价中心 |
| 通讯作者 | Huang, Cheng-gang |
| 作者单位 | 1.Chinese Acad Sci, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; 3.Nanjing Normal Univ, Nanjing 210000, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wu, Zhi-tao,Qi, Xin-ming,Sheng, Jing-jing,et al. Timosaponin A3 induces hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters[J]. ACTA PHARMACOLOGICA SINICA,2014,35(9):1188-1198. |
| APA | Wu, Zhi-tao.,Qi, Xin-ming.,Sheng, Jing-jing.,Ma, Lei-lei.,Ni, Xuan.,...&Pan, Guo-yu.(2014).Timosaponin A3 induces hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters.ACTA PHARMACOLOGICA SINICA,35(9),1188-1198. |
| MLA | Wu, Zhi-tao,et al."Timosaponin A3 induces hepatotoxicity in rats through inducing oxidative stress and down-regulating bile acid transporters".ACTA PHARMACOLOGICA SINICA 35.9(2014):1188-1198. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。