Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog
文献类型：期刊论文
| 作者 | Tian, Qianqian1,2; Jiang, Jinfang3; Yin, Hanwei4; Zhang, Yifan1 ; Li, Yilin5; Wu, Ping5; Peng, Chao5; Wang, Zhijie1; Zhou, Jialan1; Zeng, Huihui4
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| 刊名 | CURRENT DRUG METABOLISM
 |
| 出版日期 | 2022 |
| 卷号 | 23期号:11页码:928-939 |
| 关键词 | Butaselen ebselen covalent binding Se-methylation cytosol TPMT |
| ISSN号 | 1389-2002 |
| DOI | 10.2174/1389200223666220520115014 |
| 通讯作者 | Zhong, Dafang(dfzhong@simm.ac.cn) |
| 英文摘要 | Background: Butaselen is an ebselen analog that is under clinical trials for treating hepatic and pulmonary fibrosis. Our previous studies showed that butaselen is mainly present in human plasma in the form of M2, a free Se-methylated metabolite. Objective: This study aimed to investigate the metabolic mechanisms of butaselen. Methods and Results: Butaselen was incubated with human plasma. Butaselen immediately disappeared, and the butaselen-HSA (human serum albumin) adduct was detected by HPLC-HRMS, showing that butaselen covalently binds to HSA. The butaselen-HSA adduct was precipitated using acetonitrile and then incubated with PBS, Cys, and GSH for 1 hour. The product was M1, a reduced form of butaselen. The results indicated that HSA, Cys, and GSH can reduce the butaselen-HSA covalent bond. The binding site for butaselen could be the cysteine-34 residue of HSA through pronase and trypsin hydrolysis. Incubating butaselen with cysteine, butaselen-Cys, butaselen-2Cys, and M1 were generated, indicating the covalent binding and reduction of butaselen by cysteine. We incubated liver microsomes and cytosol with butaselen, 6.22 and 246 nM M2 were generated, respectively. The results demonstrated that cytosolic enzymes are mainly involved in M2 production. The amount of M2 in the liver cytosol decreased from 246 nM to 2.21 nM when 10 mM m-anisic acid (a specific TPMT enzyme inhibitor) was added, showing that TPMT is responsible for M2 formation. Conclusion: Butaselen was covalently bound to HSA, and the binding site was the cysteine-34 residue of HSA. The butaselen-HSA adduct was reduced by free thiol compounds to generate M1. M1 was further metabolized to M2 by cytosolic TPMT. This study provides a basis for studying the pharmacokinetics of selenium-containing drugs. |
| WOS关键词 | PHARMACOLOGICALLY ACTIVE METABOLITE ; MICROSOMAL THIOL METHYLTRANSFERASE ; S-METHYLTRANSFERASE ; HUMAN PLASMA ; METHYLATION ; DRUG ; CYTOCHROME-P450 ; BINDING |
| 资助项目 | National Natural Science Foundation of China[81521005] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000924540900008 |
| 出版者 | BENTHAM SCIENCE PUBL LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/303309]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Zhong, Dafang |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201210, Peoples R China 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 3.HQ Biosci Co Ltd, Suzhou 215123, Peoples R China 4.Shanghai Yuanxi Med Corp, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tian, Qianqian,Jiang, Jinfang,Yin, Hanwei,et al. Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog[J]. CURRENT DRUG METABOLISM,2022,23(11):928-939. |
| APA | Tian, Qianqian.,Jiang, Jinfang.,Yin, Hanwei.,Zhang, Yifan.,Li, Yilin.,...&Zhong, Dafang.(2022).Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog.CURRENT DRUG METABOLISM,23(11),928-939. |
| MLA | Tian, Qianqian,et al."Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog".CURRENT DRUG METABOLISM 23.11(2022):928-939. |
入库方式： OAI收割
来源：上海药物研究所
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