ArticleChemical research in toxicology2010
Selective targeting of selenocysteine in thioredoxin reductase by the half mustard 2-chloroethyl ethyl sulfide in lung epithelial cells.
Article in Chemical research in toxicology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 38 citations in OpenAlex.
- Mechanism of auranofin toxicity: Inhibition of tetrahydrobiopterin metabolism.Toxicology and applied pharmacology · 2026Article
- Current progress in research on ocular injury caused by exposure to vesicants.Progress in retinal and eye research · 2025Review
- Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1,8-Dinitropyrene and Its Metabolite 1-Amino-8-nitropyrene via Nitroreduction in Human Lung Cells.Chemical research in toxicology · 2025Article
- Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1-Nitropyrene via Nitroreduction in Human Lung Cells.Chemical research in toxicology · 2023Article
- Design, synthesis, and biological evaluation of novel derivatives of dithiodiglycolic acid prepared via oxidative coupling of thiols.Journal of enzyme inhibition and medicinal chemistry · 2019Article
- Mustard vesicant-induced lung injury: Advances in therapy.Toxicology and applied pharmacology · 2016Review
- Thioredoxin Cross-Linking by Nitrogen Mustard in Lung Epithelial Cells: Formation of Multimeric Thioredoxin/Thioredoxin Reductase Complexes and Inhibition of Disulfide Reduction.Chemical research in toxicology · 2015Article
- TrxR1 as a potent regulator of the Nrf2-Keap1 response system.Antioxidants & redox signaling · 2015Review
- Acetaminophen reactive intermediates target hepatic thioredoxin reductase.Chemical research in toxicology · 2014Article
- Cross-linking of thioredoxin reductase by the sulfur mustard analogue mechlorethamine (methylbis(2-chloroethyl)amine) in human lung epithelial cells and rat lung: selective inhibition of disulfide reduction but not redox cycling.Chemical research in toxicology · 2014Article
- Thioredoxin reductase and its inhibitors.Current protein & peptide science · 2014Review
- Susceptibility of the antioxidant selenoenyzmes thioredoxin reductase and glutathione peroxidase to alkylation-mediated inhibition by anticancer acylfulvenes.Chemical research in toxicology · 2011Article
- Sulfur mustard-induced pulmonary injury: therapeutic approaches to mitigating toxicity.Pulmonary pharmacology & therapeutics · 2011Review
- Oxidants and antioxidants in sulfur mustard-induced injury.Annals of the New York Academy of Sciences · 2010Review
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Authors and funding
7 authors at 3 institutions in 1 country.
Funding
Abstract
Thioredoxin reductase (TrxR) is a selenocysteine-containing flavoprotein that catalyzes the NADPH-dependent reduction of oxidized thioredoxin and plays a key role in regulating cellular redox homeostasis. In the present studies, we examined the effects of 2-chloroethyl ethyl sulfide (CEES), a model sulfur mustard vesicant, on TrxR in lung epithelial cells. We speculated that vesicant-induced alterations in TrxR contribute to oxidative stress and toxicity. The treatment of human lung A549 epithelial cells with CEES resulted in a time- and concentration-dependent inhibition of TrxR. Using purified rat liver TrxR, we demonstrated that only the reduced enzyme was inhibited and that this inhibition was irreversible. The reaction of TrxR with iodoacetamide, which selectively modifies free thiol or selenol on proteins, was also markedly reduced by CEES, suggesting that CEES induces covalent modification of the reduced selenocysteine-containing active site in the enzyme. This was supported by our findings that recombinant mutant TrxR, in which selenocysteine was replaced by cysteine, was markedly less sensitive to inhibition by CEES and that the vesicant preferentially alkylated selenocysteine in the C-terminal redox motif of TrxR. TrxR also catalyzes quinone redox cycling, a process that generates reactive oxygen species. In contrast to its inhibitory effects on TrxR activity, CEES was found to stimulate redox cycling. Taken together, these data suggest that sulfur mustard vesicants target TrxR and that this may be an important mechanism mediating oxidative stress and tissue injury.
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Registered trials
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