Pulmonary Toxicity and Metabolic Activation of Tetrandrine in CD-1 Mice
文献类型：期刊论文
| 作者 | Jin, Hua2; Li, Liang1 ; Zhong, Dafang1; Liu, Jia1; Chen, Xiaoyan1; Zheng, Jiang2
|
| 刊名 | CHEMICAL RESEARCH IN TOXICOLOGY
 |
| 出版日期 | 2011-12 |
| 卷号 | 24期号:12页码:2142-2152 |
| ISSN号 | 0893-228X |
| DOI | 10.1021/tx200290s |
| 文献子类 | Article |
| 英文摘要 | Tetrandrine, a bisbenzylisoquinoline alkaloid, has demonstrated promising pharmacologic activities. The alkaloid has a great potential for clinical use, so a careful, thorough toxicity evaluation of the alkaloid is required. In the present study, 24 h acute toxicity of tetrandrine was evaluated in CD-1 mice. Single intraperitoneal doses of tetrandrine at 150 mg (0.24 mmol)/kg were found to cause alveolar hemorrhage and over 3-fold elevation of lactate dehydrogenase activity in bronchoalveolar lavage fluids. Ethidium-based staining showed loss of membrane integrity in significant numbers of cells in the lungs of the animals treated with the same doses of tetrandrine. As much as 60% reduction in cell viability was observed after 24 h of exposure to tetrandrine at 40 mu M in human lung cell lines NL-20 and WI-38. Ketoconazole, an inhibitor of P450 3A, showed a protective effect on the pulmonary injury in mice given tetrandrine. A glutathione (GSH) conjugate derived from O-demethylated tetrandrine was detected in incubations of tetrandrine with NADPH- and GSH-supplemented human liver and mouse lung microsomes. The electrophilic metabolite trapped by GSH is considered to be a quinone methide derivative. The formation of the metabolite reactive to GSH was found to require the presence of NADPH. The coincubation of ketoconazole suppressed the generation of the GSH conjugate. Tetrandrine was incubated with a selection of recombinant human cytochrome P450 enzymes, and only P450s 3A4 and 3A5 were responsible for the production of the reactive metabolite. The results implicate a possible correlation between the formation of the quinone methide metabolite of tetrandrine and the pulmonary toxicity induced by tetrandrine. |
| WOS关键词 | PLANT ALKALOID TETRANDRINE ; TOPOISOMERASE-II POISON ; MULTIDRUG-RESISTANCE ; BISBENZYLISOQUINOLINE ALKALOIDS ; P-GLYCOPROTEIN ; CYTOTOXIC ACTIVITIES ; LIVER FIBROSIS ; IN-VITRO ; DAURICINE ; RATS |
| 资助项目 | National Natural Science Foundation of China[30873119] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Toxicology |
| 语种 | 英语 |
| 出版者 | AMER CHEMICAL SOC |
| WOS记录号 | WOS:000298074700008 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278311]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 200031, Peoples R China; 2.Univ Washington, Ctr Dev Therapeut, Seattle Childrens Res Inst, Div Gastroenterol & Hepatol,Dept Pediat, Seattle, WA 98101 USA |
| 推荐引用方式 GB/T 7714 | Jin, Hua,Li, Liang,Zhong, Dafang,et al. Pulmonary Toxicity and Metabolic Activation of Tetrandrine in CD-1 Mice[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2011,24(12):2142-2152. |
| APA | Jin, Hua,Li, Liang,Zhong, Dafang,Liu, Jia,Chen, Xiaoyan,&Zheng, Jiang.(2011).Pulmonary Toxicity and Metabolic Activation of Tetrandrine in CD-1 Mice.CHEMICAL RESEARCH IN TOXICOLOGY,24(12),2142-2152. |
| MLA | Jin, Hua,et al."Pulmonary Toxicity and Metabolic Activation of Tetrandrine in CD-1 Mice".CHEMICAL RESEARCH IN TOXICOLOGY 24.12(2011):2142-2152. |
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。