Critical Role of Hepatic Cyp450 sin the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice
文献类型：期刊论文
| 作者 | Yu, Cunzhi2,3; Li, Yu2,3; Liu, Mingxia2,3; Gao, Man2,3; Li, Chenggang2,3; Yan, Hong2,3; Li, Chunzhu2,3; Sun, Lihan1; Mo, Liying1; Wu, Chunyong1 |
| 刊名 | FRONTIERS IN PHARMACOLOGY
 |
| 出版日期 | 2017-11-21 |
| 卷号 | 8 |
| 关键词 | (5R)-5-hydroxytriptolide functional knockout cytochrome P450 testes gamma-H2AX RNA polymerase II androgen receptor |
| ISSN号 | 1663-9812 |
| DOI | 10.3389/fphar.2017.00832 |
| 文献子类 | Article |
| 英文摘要 | Low solubility, tissue accumulation, and toxicity are chief obstacles to developing triptolide derivatives, so a better understanding of the pharmacokinetics and toxicity of triptolide derivatives will help with these limitations. To address this, we studied pharmacokinetics and toxicity of (5R)-5-hydroxytriptolide (LLDT-8), a novel triptolide derivative immunosuppressant in a conditional knockout (KO) mouse model with liver-specific deletion of CYP450 reductase. Compared to wild type (WT) mice, after LLDT-8 treatment, KO mice suffered severe testicular toxicity (decreased testicular weight, spermatocytes apoptosis) unlike WT mice. Moreover, KO mice had greater LLDT-8 exposure as confirmed with elevated AUC and Cmax, increased drug half-life, and greater tissue distribution. gamma-H2AX, a marker of meiosis process, its localization and protein level in testis showed a distinct meiosis block induced by LLDT-8. RNA polymerase II (Pol II), an essential factor for RNA storage and synapsis in spermatogenesis, decreased in testes of KO mice after LLDT-8 treatment. Germ-cell line based assays confirmed that LLDT-8 selectively inhibited Pol II in spermatocyte-like cells. Importantly, the analysis of androgen receptor (AR) related genes showed that LLDT-8 did not change AR-related signaling in testes. Thus, hepatic CYP450s were responsible for in vivo metabolism and clearance of LLDT-8 and aggravated testicular injury may be due to increased LLDT-8 exposure in testis and subsequent Pol II reduction. |
| WOS关键词 | NATURAL-PRODUCT TRIPTOLIDE ; GENE-EXPRESSION ; CELL-DEATH ; IN-VITRO ; ANDROGEN RECEPTOR ; REDUCTASE GENE ; P-GLYCOPROTEIN ; CANCER-CELLS ; INHIBITION ; APOPTOSIS |
| 资助项目 | National Natural Science Foundation of China[81102496] ; National Key Technologies RD Program[2015ZX09102005] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000415798900001 |
| 出版者 | FRONTIERS MEDIA SA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/272398]  |
| 专题 | 药物安全性评价中心 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 |
| 通讯作者 | Qi, Xinming |
| 作者单位 | 1.China Pharmaceut Univ, Dept Pharmaceut Anal, Nanjing, Jiangsu, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Safety Evaluat & Res, State Key Lab Drug Res, Shanghai, Peoples R China; 3.Univ Chinese Acad Sci, Beijing, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Yu, Cunzhi,Li, Yu,Liu, Mingxia,et al. Critical Role of Hepatic Cyp450 sin the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice[J]. FRONTIERS IN PHARMACOLOGY,2017,8. |
| APA | Yu, Cunzhi.,Li, Yu.,Liu, Mingxia.,Gao, Man.,Li, Chenggang.,...&Ren, Jin.(2017).Critical Role of Hepatic Cyp450 sin the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice.FRONTIERS IN PHARMACOLOGY,8. |
| MLA | Yu, Cunzhi,et al."Critical Role of Hepatic Cyp450 sin the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice".FRONTIERS IN PHARMACOLOGY 8(2017). |
入库方式： OAI收割
来源：上海药物研究所
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