RGD Reference Report - Ebselen, a seleno-organic antioxidant, as an electrophile. - Rat Genome Database

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Ebselen, a seleno-organic antioxidant, as an electrophile.

Authors: Sakurai, T  Kanayama, M  Shibata, T  Itoh, K  Kobayashi, A  Yamamoto, M  Uchida, K 
Citation: Sakurai T, etal., Chem Res Toxicol. 2006 Sep;19(9):1196-204.
RGD ID: 6902921
Pubmed: PMID:16978024   (View Abstract at PubMed)
DOI: DOI:10.1021/tx0601105   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
selenium compound metabolic process  IEP 6902921ebselenRGD 

Objects Annotated

Genes (Rattus norvegicus)
Keap1  (Kelch-like ECH-associated protein 1)


Additional Information