Document Detail

Ebselen, a seleno-organic antioxidant, as an electrophile.
MedLine Citation:
PMID:  16978024     Owner:  NLM     Status:  MEDLINE    
Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a seleno-organic compound showing glutathione peroxidase-like activity, is one of the promising synthetic antioxidants. In the present study, we investigated the electrophilic potential of this antioxidant and established the mechanism of the cysteine-targeted oxidation of protein. In addition, using ebselen as an electrophilic probe, we characterized the cysteine residues required for posttranslational modification into an electrophile sensor protein in the phase 2 detoxification response. Ebselen showed a potent antioxidant effect against the spontaneous and 4-hydroxy-2-nonenal-stimulated production of intracellular reactive oxygen species in rat liver epithelial RL34 cells. Meanwhile, upon in vitro incubation with a redox-active sulfhydryl protein (thioredoxin), ebselen showed a strong electrophilic potential of mediating the formation of selenenylsulfide and intra- and intermolecular disulfide linkages within the protein. By taking advantage of this antioxidant and electrophilic property of ebselen, we characterized posttranslational modification of Kelch-like ECH-associated protein 1 (Keap1), an electrophile sensor protein, which represses the ability of the transcription factor NF-E2-related factor 2 (Nrf2) upon induction of the phase 2 detoxification response. Ebselen potently induced the gene expression of a series of phase 2 enzymes in rat liver epithelial RL34 cells, which was associated with the formation of a high molecular weight complex of Keap1. Furthermore, a cysteine residue in Keap1, C151, was found to be uniquely required not only for the formation of the complex but also for the induction of the phase 2 response by ebselen. Thus, this unique antioxidant and electrophilic property of ebselen giving rise to the cysteine-targeted oxidation enabled us to evaluate the role of sensor cysteines in redox regulation of protein function under electrophile stress.
Toyo Sakurai; Masaya Kanayama; Takahiro Shibata; Ken Itoh; Akira Kobayashi; Masayuki Yamamoto; Koji Uchida
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Chemical research in toxicology     Volume:  19     ISSN:  0893-228X     ISO Abbreviation:  Chem. Res. Toxicol.     Publication Date:  2006 Sep 
Date Detail:
Created Date:  2006-09-18     Completed Date:  2006-11-13     Revised Date:  2006-12-21    
Medline Journal Info:
Nlm Unique ID:  8807448     Medline TA:  Chem Res Toxicol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1196-204     Citation Subset:  IM    
Graduate School of Bioagricultural Sciences, Nagoya University, Nagoya 464-8601, Japan.
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MeSH Terms
Antioxidants / chemistry*
Azoles / chemistry*
Cell Line
Electrophoresis, Gel, Two-Dimensional
Flow Cytometry
Organoselenium Compounds / chemistry*
Reactive Oxygen Species / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Reg. No./Substance:
0/Antioxidants; 0/Azoles; 0/Organoselenium Compounds; 0/Reactive Oxygen Species; 60940-34-3/ebselen
Erratum In:
Chem Res Toxicol. 2006 Nov;19(11):1557

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