Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4
文献类型：期刊论文
| 作者 | Yu, Jinghua; Deng, Pan; Zhong, Dafang ; Chen, Xiaoyan
|
| 刊名 | CHEMICAL RESEARCH IN TOXICOLOGY
 |
| 出版日期 | 2014-09 |
| 卷号 | 27期号:9页码:1598-1609 |
| ISSN号 | 0893-228X |
| DOI | 10.1021/tx5002145 |
| 文献子类 | Article |
| 英文摘要 | Toosendanin (TSN) is a hepatotoxic triterpenoid extracted from Melia toosendan Sieb et Zucc. Considering that TSN contains the structural alert of the furan ring, it is believed that bioactivation of TSN may be responsible for its toxicity. Herein, the bioactivation potential and metabolism profiles of TSN were investigated. After an oral administration of 10 mg/kg TSN to rats, esterolysis and conjugation with amino acids were identified as the main metabolic pathways. The same types of conjugates were detected in liver microsomes in an NADPH-dependent manner. According to the remaining amount of the parent drug, the reactivity of trapping reagents with TSN reactive metabolites was sorted in a decreasing order of N-alpha-(tert-butoxycarbonyl)-l-lysine (Boc-Lys) > alanine, lysine, taurine, phenylalanine, serine, glutamic acid, glycine, and glutathione (GSH) > cysteine. No conjugates were observed in NADPH and N-acetyl cysteine (NAC)-supplemented human liver microsomal incubations. Further phenotyping studies and the chemical synthesis of the major conjugated standards proved that TSN was bioactivated by CYP3A4 and yielded a cis-butene-1,4-dial intermediate, which was prone to undergo 1,2-addition with the amino group of amino acids and GSH to form 3-pyrroline-2-one adducts. The sulfydryl group of GSH also attacked the intermediate and yielded S-conjugates by 1,4- or 1,2-addition, which would form pyrrole conjugates by further reacting with the amino group. Compared to the well-recognized S-conjugation of the furan ring, N-conjugation with multiple amino acids and GSH played a more important part in the elimination of reactive metabolites of TSN. The significance of these conjugates requires further investigation. |
| WOS关键词 | REACTIVE METABOLITE ; TEUCRIN-A ; IN-VITRO ; (R)-(+)-MENTHOFURAN ; ACTIVATION ; ADDUCTS ; VIVO ; RATS |
| 资助项目 | National Natural Science Foundation of China[81202579] ; National Natural Science Foundation of China[81173115] |
| WOS研究方向 | Pharmacology & Pharmacy ; Chemistry ; Toxicology |
| 语种 | 英语 |
| WOS记录号 | WOS:000341747600014 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276918]  |
| 专题 | 上海药物代谢研究中心 |
| 通讯作者 | Chen, Xiaoyan |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Yu, Jinghua,Deng, Pan,Zhong, Dafang,et al. Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4[J]. CHEMICAL RESEARCH IN TOXICOLOGY,2014,27(9):1598-1609. |
| APA | Yu, Jinghua,Deng, Pan,Zhong, Dafang,&Chen, Xiaoyan.(2014).Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4.CHEMICAL RESEARCH IN TOXICOLOGY,27(9),1598-1609. |
| MLA | Yu, Jinghua,et al."Identification of Amino Acid and Glutathione N-Conjugates of Toosendanin: Bioactivation of the Furan Ring Mediated by CYP3A4".CHEMICAL RESEARCH IN TOXICOLOGY 27.9(2014):1598-1609. |
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。