Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity
文献类型：期刊论文
| 作者 | Xue, Xiang2; Gong, Likun2 ; Qi, Xinming2; Wu, Yuanfeng2; Xing, Guozhen2; Yao, Jun2; Luan, Yang2; Xiao, Ying2; Li, Yan2; Wu, Xiongfei2
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| 刊名 | TOXICOLOGY LETTERS
 |
| 出版日期 | 2011-08-10 |
| 卷号 | 205期号:1页码:47-54 |
| ISSN号 | 0378-4274 |
| 关键词 | Triptolide Cytochrome P450 Xenobiotic metabolism Toxicity |
| DOI | 10.1016/j.toxlet.2011.05.003 |
| 文献子类 | Article |
| 英文摘要 | Triptolide, the primary active component of Tripterygium wilfordii Hook F. has various pharmacological activities but also a narrow therapeutic window. Cytochrome P450s are proposed to be responsible for the hydroxylation of triptolide in vitro and CYP3A induction by dexamethasone can increase the metabolism of triptolide and decrease the hepatotoxicity in rat. However, triptolide-induced toxicity has not been investigated in an animal model having a suppression of P450 activities. Here we compared the toxicological effects and toxicokinetics of triptolide between liver-specific cytochrome P450 reductase (CPR) knockout (KO) mice (abolished hepatic P450 activities) and wild-type (WT) control mice after a single oral gavage of triptolide at 0.5 mg/kg or 1.0 mg/kg. A low toxic dose of triptolide at 0.5 mg/kg for WT mice resulted in severe toxicities including death in KO mice. Changes in serum biochemistry, hematology and histopathology further indicated much more severe toxicities in multiple organs in KO mice compared to WT mice after triptolide administration. The mono-hydroxylated metabolites of triptolide detected in the blood of WT mice were undetectable in KO mice, accompanied by much higher triptolide levels in the blood and tissues including the liver, kidney, and spleen determined by LC-MS/MS. Taken together, our results confirmed that inactivation of hepatic P450s abolishes the ability in metabolism of triptolide in the liver, subsequently resulting in an increase in bioavailability and toxicity of triptolide in vivo. It is suggested that P450 inhibition/inactivation might pose a significant health risk in the clinic use of triptolide. (C) 2011 Elsevier Ireland Ltd. All rights reserved. |
| WOS关键词 | TRIPTERYGIUM-WILFORDII ; IN-VIVO ; HOOK-F ; CYTOCHROME-P450 ; POLYMORPHISMS ; ARTHRITIS ; DELETION ; KIDNEY ; CELLS ; GENE |
| 资助项目 | National Grand Fundamental Research 973 Program of China[2006CB504700] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2009ZX09301-001] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2008ZX09305-007] ; National Science and Technology Major Project "Key New Drug Creation and Manufacturing Program", China[2009ZX09501-033] |
| WOS研究方向 | Toxicology |
| 语种 | 英语 |
| 出版者 | ELSEVIER IRELAND LTD |
| WOS记录号 | WOS:000293321200006 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278445]  |
| 专题 | 药物安全性评价中心 |
| 通讯作者 | Gong, Likun |
| 作者单位 | 1.SUNY Albany, Wadsworth Ctr, New York State Dept Hlth, Albany, NY 12222 USA; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab New Drug Res, Shanghai 200031, Peoples R China; 3.SUNY Albany, Sch Publ Hlth, Albany, NY USA |
| 推荐引用方式 GB/T 7714 | Xue, Xiang,Gong, Likun,Qi, Xinming,et al. Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity[J]. TOXICOLOGY LETTERS,2011,205(1):47-54. |
| APA | Xue, Xiang.,Gong, Likun.,Qi, Xinming.,Wu, Yuanfeng.,Xing, Guozhen.,...&Ren, Jin.(2011).Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity.TOXICOLOGY LETTERS,205(1),47-54. |
| MLA | Xue, Xiang,et al."Knockout of hepatic P450 reductase aggravates triptolide-induced toxicity".TOXICOLOGY LETTERS 205.1(2011):47-54. |
入库方式： OAI收割
来源：上海药物研究所
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