ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes
文献类型：期刊论文
| 作者 | Qi, Xin-ming ; Miao, Ling-ling; Cai, Yan; Gong, Li-kun; Ren, Jin
|
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2013-09 |
| 卷号 | 34期号:9页码:1229-1236 |
| 关键词 | tetrandrine mitochondria reactive oxygen species cytochrome P450 |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2013.62 |
| 文献子类 | Article |
| 英文摘要 | Aim: Tetrandrine, an alkaloid with a remarkable pharmacological profile, induces oxidative stress and mitochondrial dysfunction in hepatocytes; however, mitochondria are not the direct target of tetrandrine, which prompts us to elucidate the role of oxidative stress in tetrandrine-induced mitochondrial dysfunction and the sources of oxidative stress. Methods: Rat primary hepatocytes were isolated by two-step collagenase perfusion. Mitochondrial function was evaluated by analyzing ATP content, mitochondrial membrane potential (MMP) and the mitochondrial permeability transition. The oxidative stress was evaluated by examining changes in the levels of reactive oxygen species (ROS) and glutathione (GSH). Results: ROS scavengers largely attenuated the cytotoxicity induced by tetrandrine in rat hepatocytes, indicating the important role of ROS in the hepatotoxicity of tetrandrine. Of the multiple ROS inhibitors that were tested, only inhibitors of CYP450 (SKF-525A and others) reduced the ROS levels and ameliorated the depletion of GSH. Mitochondrial function assays showed that the mitochondrial permeability transition (MPT) induced by tetrandrine was inhibited by SKF-525A and vitamin C (VC), both of which also rescued the depletion of ATP levels and the mitochondrial membrane potential. Upon inhibiting specific CYP450 isoforms, we observed that the inhibitors of CYP2D, CYP2C, and CYP2E1 attenuated the ATP depletion that occurred following tetrandrine exposure, whereas the inhibitors of CYP2D and CYP2E1 reduced the ROS induced by tetrandrine. Overexpression of CYP2E1 enhanced the tetrandrine-induced cytotoxicity. Conclusion: We demonstrated that CYP450 plays an important role in the mitochondrial dysfunction induced by the administration of tetrandrine. ROS generated by CYP450, especially CYP2E1, may contribute to the mitochondrial dysfunction induced by tetrandrine. |
| WOS关键词 | FATTY LIVER-DISEASE ; KAPPA-B PATHWAY ; OXIDATIVE STRESS ; PERMEABILITY TRANSITION ; CYTOCHROME-P450 2E1 ; INDUCED APOPTOSIS ; CELL-DEATH ; ER-STRESS ; ACTIVATION ; INJURY |
| 资助项目 | National Natural Science Foundation of China[30271558] ; Key Projects of National Science and Technology Pillar Program[2012ZX09301001-006] ; Key Projects of National Science and Technology Pillar Program[2012zx09302003] ; Public Service Platform Project of Shanghai Science and Technology Committee[11DZ2292500] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4921450 |
| WOS记录号 | WOS:000324170400013 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277477]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Gong, Li-kun |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Qi, Xin-ming,Miao, Ling-ling,Cai, Yan,et al. ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes[J]. ACTA PHARMACOLOGICA SINICA,2013,34(9):1229-1236. |
| APA | Qi, Xin-ming,Miao, Ling-ling,Cai, Yan,Gong, Li-kun,&Ren, Jin.(2013).ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes.ACTA PHARMACOLOGICA SINICA,34(9),1229-1236. |
| MLA | Qi, Xin-ming,et al."ROS generated by CYP450, especially CYP2E1, mediate mitochondrial dysfunction induced by tetrandrine in rat hepatocytes".ACTA PHARMACOLOGICA SINICA 34.9(2013):1229-1236. |
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。