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Current Drug Metabolism

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ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

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Research Article

Investigating the Metabolic Mechanisms of Butaselen, An Ebselen Analog

Author(s): Qianqian Tian, Jinfang Jiang, Hanwei Yin, Yifan Zhang, Yilin Li, Ping Wu, Chao Peng, Zhijie Wang, Jialan Zhou, Huihui Zeng and Dafang Zhong*

Volume 23, Issue 11, 2022

Published on: 22 June, 2022

Page: [928 - 939] Pages: 12

DOI: 10.2174/1389200223666220520115014

Price: $65

Abstract

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.

Keywords: Butaselen, ebselen, covalent binding, Se-methylation, cytosol, TPMT.

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