Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice
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-h...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2017-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fphar.2017.00832/full |
| _version_ | 1811264731942486016 |
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| author | Cunzhi Yu Cunzhi Yu Yu Li Yu Li Mingxia Liu Mingxia Liu Man Gao Man Gao Chenggang Li Chenggang Li Hong Yan Hong Yan Chunzhu Li Chunzhu Li Lihan Sun Liying Mo Chunyong Wu Xinming Qi Xinming Qi Jin Ren Jin Ren |
| author_facet | Cunzhi Yu Cunzhi Yu Yu Li Yu Li Mingxia Liu Mingxia Liu Man Gao Man Gao Chenggang Li Chenggang Li Hong Yan Hong Yan Chunzhu Li Chunzhu Li Lihan Sun Liying Mo Chunyong Wu Xinming Qi Xinming Qi Jin Ren Jin Ren |
| author_sort | Cunzhi Yu |
| collection | DOAJ |
| description | 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. γ-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. |
| first_indexed | 2024-04-12T20:09:37Z |
| format | Article |
| id | doaj.art-e8e79ec23e5c4a9581583f17a08213b1 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T20:09:37Z |
| publishDate | 2017-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e8e79ec23e5c4a9581583f17a08213b12022-12-22T03:18:17ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122017-11-01810.3389/fphar.2017.00832295701Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 MiceCunzhi Yu0Cunzhi Yu1Yu Li2Yu Li3Mingxia Liu4Mingxia Liu5Man Gao6Man Gao7Chenggang Li8Chenggang Li9Hong Yan10Hong Yan11Chunzhu Li12Chunzhu Li13Lihan Sun14Liying Mo15Chunyong Wu16Xinming Qi17Xinming Qi18Jin Ren19Jin Ren20Center for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaDepartment of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaCenter for Drug Safety Evaluation and Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, ChinaUniversity of Chinese Academy of Sciences, Beijing, ChinaLow 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. γ-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.http://journal.frontiersin.org/article/10.3389/fphar.2017.00832/full(5R)-5-hydroxytriptolidefunctional knockoutcytochrome P450testesγ-H2AXRNA polymerase II |
| spellingShingle | Cunzhi Yu Cunzhi Yu Yu Li Yu Li Mingxia Liu Mingxia Liu Man Gao Man Gao Chenggang Li Chenggang Li Hong Yan Hong Yan Chunzhu Li Chunzhu Li Lihan Sun Liying Mo Chunyong Wu Xinming Qi Xinming Qi Jin Ren Jin Ren Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice Frontiers in Pharmacology (5R)-5-hydroxytriptolide functional knockout cytochrome P450 testes γ-H2AX RNA polymerase II |
| title | Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice |
| title_full | Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice |
| title_fullStr | Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice |
| title_full_unstemmed | Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice |
| title_short | Critical Role of Hepatic Cyp450s in the Testis-Specific Toxicity of (5R)-5-Hydroxytriptolide in C57BL/6 Mice |
| title_sort | critical role of hepatic cyp450s in the testis specific toxicity of 5r 5 hydroxytriptolide in c57bl 6 mice |
| topic | (5R)-5-hydroxytriptolide functional knockout cytochrome P450 testes γ-H2AX RNA polymerase II |
| url | http://journal.frontiersin.org/article/10.3389/fphar.2017.00832/full |
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