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Arne Holmgren - One of the best experts on this subject based on the ideXlab platform.
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Topical Therapeutic Efficacy of Ebselen Against Multidrug-Resistant Staphylococcus aureus LT-1 Targeting Thioredoxin Reductase.
Frontiers in microbiology, 2020Co-Authors: Chuanjiang Dong, Arne Holmgren, Jingxuan Zhou, Peng Wang, Ying Zhao, Xiaoyuan Ren, Jun Wang, Lili ZouAbstract:As a thiol-dependent enzyme, thioredoxin reductase (TrxR) is a promising antibacterial drug target. Ebselen, an organo-selenium with well-characterized toxicology and pharmacology, was recently reported to have potent antibacterial activity against Staphylococcus aureus. In this paper, we demonstrated that Ebselen has strong bactericidal activity against multidrug-resistant (MDR) S. aureus based on taking TrxR as a major target and disruption of the redox microenvironment. Further, the topical therapeutic efficacy of Ebselen for staphylococcal skin infections was assessed in a rat model. Treatment with Ebselen significantly reduced the bacterial load and the expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) in S. aureus skin lesions; further, wound healing and pathological changes were obvious improved in Ebselen-treated rats compare to controls. Finally, Ebselen was found to sensitize S. aureus to curcumin, which may be due to their synergistic effects in inhibiting bacterial TrxR. Altogether, Ebselen is an effective topical antibacterial agent in animal model of MDR S. aureus LT-1 skin infection. This may lay the foundation for further analysis and development of Ebselen as an antibacterial agent for topical treatment of MDR staphylococcal infections.
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Ebselen: A thioredoxin reductase-dependent catalyst for α-tocopherol quinone reduction
Toxicology and Applied Pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:Abstract The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if α-tocopherol quinone (TQ), a product of α-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, α-tocopherolhydroquinone (TQH 2 ), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
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Ebselen: a thioredoxin reductase-dependent catalyst for alpha-tocopherol quinone reduction.
Toxicology and applied pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if alpha-tocopherol quinone (TQ), a product of alpha-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, alpha-tocopherolhydroquinone (TQH(2)), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
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Ebselen is a dehydroascorbate reductase mimic, facilitating the recycling of ascorbate via mammalian thioredoxin systems.
Antioxidants & redox signaling, 2004Co-Authors: Rong Zhao, Arne HolmgrenAbstract:Ebselen is a selanazal drug recently revealed as a highly efficient peroxiredoxin mimic catalyzing the hydroperoxide reduction by the mammalian thioredoxin system [thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH]. The mammalian Trx system is a dehydroascorbic acid reductase recycling ascorbic acid essential for cell functions. Here we report that Ebselen strongly facilitated the recycling of ascorbic acid by the TrxR both with and without Trx present. Reduction of dehydroascorbic acid by TrxR has a pH optimum of 6.4, and only ~55% of this activity at a physiological pH of 7.4. Ebselen at 6 µM enhances this reaction three-fold and with the same pH optimum of 6.4. The mechanism of the Ebselen effect is suggested to involve reduction of dehydroascorbic acid by the Ebselen selenol, a highly efficient two-electron reductant. Thus, Ebselen acts as an antioxidant to lower the peroxide tone inside cells and to facilitate the recycling of dehydroascorbic acid to ascorbic acid, so as to increase the radi...
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a novel antioxidant mechanism of Ebselen involving Ebselen diselenide a substrate of mammalian thioredoxin and thioredoxin reductase
Journal of Biological Chemistry, 2002Co-Authors: Rong Zhao, Arne HolmgrenAbstract:Abstract The antioxidant mechanism of Ebselen involves recently discovered reductions by mammalian thioredoxin reductase (TrxR) and thioredoxin (Trx) forming Ebselen selenol. Here we describe a previously unknown reaction; Ebselen reacts with its selenol forming an Ebselen diselenide with a rate constant of 372 m −1s−1. The diselenide also was a substrate of TrxR forming the selenol withK m of 40 μm andk cat of 79 min−1(k cat/K m of 3.3 × 104 m −1s−1). Trx increased the reduction because of its fast reaction with diselenide (rate constant 1.7 × 103 m −1s−1). Diselenide stimulated the H2O2 reductase activity of TrxR, even more efficiently with Trx present. Because the mechanism of Ebselen as an antioxidant has been assumed to involve glutathione peroxidase-like activity, we compared the H2O2 reductase activity of Ebselen with the GSH and Trx systems. TrxR at 50 nm, far below the estimated physiological level, gave 8-fold higher activity compared with 1 mm GSH; addition of 5 μm Trx increased this difference to 13-fold. The rate constant of Ebselen selenol reacting with H2O2was estimated to be faster than 350m −1s−1. We propose novel mechanisms for Ebselen antioxidant action involving Ebselen selenol and diselenide formation, with the thioredoxin system rather than glutathione as the predominant effector and target.
Rong Zhao - One of the best experts on this subject based on the ideXlab platform.
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Ebselen: A thioredoxin reductase-dependent catalyst for α-tocopherol quinone reduction
Toxicology and Applied Pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:Abstract The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if α-tocopherol quinone (TQ), a product of α-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, α-tocopherolhydroquinone (TQH 2 ), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
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Ebselen: a thioredoxin reductase-dependent catalyst for alpha-tocopherol quinone reduction.
Toxicology and applied pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if alpha-tocopherol quinone (TQ), a product of alpha-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, alpha-tocopherolhydroquinone (TQH(2)), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
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Ebselen is a dehydroascorbate reductase mimic, facilitating the recycling of ascorbate via mammalian thioredoxin systems.
Antioxidants & redox signaling, 2004Co-Authors: Rong Zhao, Arne HolmgrenAbstract:Ebselen is a selanazal drug recently revealed as a highly efficient peroxiredoxin mimic catalyzing the hydroperoxide reduction by the mammalian thioredoxin system [thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH]. The mammalian Trx system is a dehydroascorbic acid reductase recycling ascorbic acid essential for cell functions. Here we report that Ebselen strongly facilitated the recycling of ascorbic acid by the TrxR both with and without Trx present. Reduction of dehydroascorbic acid by TrxR has a pH optimum of 6.4, and only ~55% of this activity at a physiological pH of 7.4. Ebselen at 6 µM enhances this reaction three-fold and with the same pH optimum of 6.4. The mechanism of the Ebselen effect is suggested to involve reduction of dehydroascorbic acid by the Ebselen selenol, a highly efficient two-electron reductant. Thus, Ebselen acts as an antioxidant to lower the peroxide tone inside cells and to facilitate the recycling of dehydroascorbic acid to ascorbic acid, so as to increase the radi...
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a novel antioxidant mechanism of Ebselen involving Ebselen diselenide a substrate of mammalian thioredoxin and thioredoxin reductase
Journal of Biological Chemistry, 2002Co-Authors: Rong Zhao, Arne HolmgrenAbstract:Abstract The antioxidant mechanism of Ebselen involves recently discovered reductions by mammalian thioredoxin reductase (TrxR) and thioredoxin (Trx) forming Ebselen selenol. Here we describe a previously unknown reaction; Ebselen reacts with its selenol forming an Ebselen diselenide with a rate constant of 372 m −1s−1. The diselenide also was a substrate of TrxR forming the selenol withK m of 40 μm andk cat of 79 min−1(k cat/K m of 3.3 × 104 m −1s−1). Trx increased the reduction because of its fast reaction with diselenide (rate constant 1.7 × 103 m −1s−1). Diselenide stimulated the H2O2 reductase activity of TrxR, even more efficiently with Trx present. Because the mechanism of Ebselen as an antioxidant has been assumed to involve glutathione peroxidase-like activity, we compared the H2O2 reductase activity of Ebselen with the GSH and Trx systems. TrxR at 50 nm, far below the estimated physiological level, gave 8-fold higher activity compared with 1 mm GSH; addition of 5 μm Trx increased this difference to 13-fold. The rate constant of Ebselen selenol reacting with H2O2was estimated to be faster than 350m −1s−1. We propose novel mechanisms for Ebselen antioxidant action involving Ebselen selenol and diselenide formation, with the thioredoxin system rather than glutathione as the predominant effector and target.
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Ebselen a substrate for human thioredoxin reductase strongly stimulating its hydroperoxide reductase activity and a superfast thioredoxin oxidant
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Rong Zhao, Hiroyuki Masayasu, Arne HolmgrenAbstract:Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], a seleno-organic compound with glutathione peroxidase-like activity is used in clinical trials against stroke. Human and bovine TrxR catalyzed the reduction of Ebselen to Ebselen selenol by NADPH with an apparent K(M)-value of 2.5 microM and a kcat of 588 min(-1). The addition of thioredoxin (Trx) stimulated the TrxR-catalyzed reduction of Ebselen several-fold. This result was caused by a very fast oxidation of reduced Trx by Ebselen with a rate constant in excess of 2 x 10(7) M(-1) s(-1). This rate is orders of magnitude faster than the reaction of dithiol Trx with insulin disulfides. Ebselen competed with disulfide substrates for reduction by Trx and, therefore, acted as an inhibitor of protein disulfide reduction by the Trx system. The inherent H2O2 reductase activity of mammalian TrxR dependent on its active-site selenocysteine residue was stimulated 10-fold by 2 microM Ebselen and 25-fold in the additional presence of 5 microM Trx. Furthermore, the apparent K(M)-value of TrxR for H2O2 was lowered 25-fold to about 100 microM. Our results demonstrate that Ebselen is a TrxR peroxidase which, in the presence of Trx, acted as a mimic of a peroxiredoxin. The activity with TrxR and oxidation of reduced Trx offer mechanistic explanations for the in vivo effects of Ebselen as an antioxidant and anti-inflammatory agent. Our results demonstrate that the mechanism of action of Ebselen may be predominantly via the Trx system rather than via glutathione.
Mohamed N Seleem - One of the best experts on this subject based on the ideXlab platform.
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evaluation of Ebselen in resolving a methicillin resistant staphylococcus aureus infection of pressure ulcers in obese and diabetic mice
PLOS ONE, 2021Co-Authors: Haroon Mohammad, Nader S Abutaleb, Alexandra M Dieterly, Tiffany L Lyle, Mohamed N SeleemAbstract:Pressure ulcers (PUs) are a source of morbidity in individuals with restricted mobility including individuals that are obese or diabetic. Infection of PUs with pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), impairs ulcers from healing. The present study evaluated Ebselen as a topical antibacterial to treat MRSA-infected PUs. Against two different S. aureus strains, including MRSA USA300, resistance to Ebselen did not emerge after 14 consecutive passages. Resistance to mupirocin emerged after only five passages. Additionally, Ebselen was found to exert a modest postantibiotic effect of five hours against two MRSA strains. Ebselen was subsequently evaluated in MRSA-infected PUs in two models using obese and diabetic mice. In obese mice, topical Ebselen (89.2% reduction) and oral linezolid (84.5% reduction) similarly reduced the burden of MRSA in infected PUs. However, in diabetic mice, topical Ebselen (45.8% reduction in MRSA burden) was less effective. Histopathological evaluation of ulcers in diabetic mice determined that Ebselen treatment resulted in fewer bacterial colonies deep within the dermis and that the treatment exhibited evidence of epithelial regeneration. Topical mupirocin was superior to Ebselen in reducing MRSA burden in infected PUs both in obese (98.7% reduction) and diabetic (99.3% reduction) mice. Ebselen's antibacterial activity was negatively impacted as the bacterial inoculum was increased from 105 CFU/mL to 107 CFU/mL. These results suggest that a higher dose of Ebselen, or a longer course of treatment, may be needed to achieve a similar effect as mupirocin in topically treating MRSA-infected pressure ulcers.
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Ebselen exerts antifungal activity by regulating glutathione gsh and reactive oxygen species ros production in fungal cells
Biochimica et Biophysica Acta, 2017Co-Authors: Shankar Thangamani, Hassan E Eldesouky, Haroon Mohammad, Pete E Pascuzzi, Larisa Avramova, Tony R Hazbun, Mohamed N SeleemAbstract:Abstract Background Ebselen, an organoselenium compound and a clinically safe molecule has been reported to possess potent antifungal activity, but its antifungal mechanism of action and in vivo antifungal activity remain unclear. Methods The antifungal effect of Ebselen was tested against Candida albicans, C. glabrata, C. tropicalis, C. parapsilosis, Cryptococcus neoformans, and C. gattii clinical isolates. Chemogenomic profiling and biochemical assays were employed to identify the antifungal target of Ebselen. Ebselen's antifungal activity in vivo was investigated in a Caenorhabditis elegans animal model. Results Ebselen exhibits potent antifungal activity against both Candida spp. and Cryptococcus spp., at concentrations ranging from 0.5 to 2 μg/ml. Ebselen rapidly eradicates a high fungal inoculum within 2 h of treatment. Investigation of the drug's antifungal mechanism of action indicates that Ebselen depletes intracellular glutathione (GSH) levels, leading to increased production of reactive oxygen species (ROS), and thereby disturbs the redox homeostasis in fungal cells. Examination of Ebselen's in vivo antifungal activity in two Caenorhabditis elegans models of infection demonstrate that Ebselen is superior to conventional antifungal drugs (fluconazole, flucytosine and amphotericin) in reducing Candida and Cryptococcus fungal load. Conclusion Ebselen possesses potent antifungal activity against clinically relevant isolates of both Candida and Cryptococcus by regulating GSH and ROS production. The potent in vivo antifungal activity of Ebselen supports further investigation for repurposing it for use as an antifungal agent. General significance The present study shows that Ebselen targets glutathione and also support that glutathione as a potential target for antifungal drug development.
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Repurposing Ebselen for treatment of multidrug-resistant staphylococcal infections
Scientific reports, 2015Co-Authors: Shankar Thangamani, Waleed Younis, Mohamed N SeleemAbstract:Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that Ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, Ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of Ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that Ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of Ebselen as a potential treatment for multidrug-resistant staphylococcal infections.
Yang Tang - One of the best experts on this subject based on the ideXlab platform.
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aglycone Ebselen and β d xyloside primed glycosaminoglycans co contribute to Ebselen β d xyloside induced cytotoxicity
Journal of Medicinal Chemistry, 2018Co-Authors: Yang Tang, Siqi Zhang, Yajing Chang, Dacheng Fan, Ariane De Agostini, Lijuan Zhang, Tao JiangAbstract:Most β-d-xylosides with hydrophobic aglycones are nontoxic primers for glycosaminoglycan assembly in animal cells. However, when Ebselen was conjugated to d-xylose, d-glucose, d-galactose, and d-lactose (8A–D), only Ebselen β-d-xyloside (8A) showed significant cytotoxicity in human cancer cells. The following facts indicated that the aglycone Ebselen and β-d-xyloside primed glycosaminoglycans co-contributed to the observed cytotoxicity: 1. Ebselen induced S phase cell cycle arrest, whereas 8A induced G2/M cell cycle arrest; 2. 8A augmented early and late phase cancer cell apoptosis significantly compared to that of Ebselen and 8B–D; 3. Both 8A and phenyl-β-d-xyloside primed glycosaminoglycans with similar disaccharide compositions in CHO-pgsA745 cells; 4. Glycosaminoglycans could be detected inside of cells only when treated with 8A, indicating Ebselen contributed to the unique property of intracellular localization of the primed glycosaminoglycans. Thus, 8A represents a lead compound for the development ...
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Aglycone Ebselen and β‑d‑Xyloside Primed Glycosaminoglycans Co-contribute to Ebselen β‑d‑Xyloside-Induced Cytotoxicity
2018Co-Authors: Yang Tang, Siqi Zhang, Yajing Chang, Dacheng Fan, Ariane De Agostini, Lijuan Zhang, Tao JiangAbstract:Most β-d-xylosides with hydrophobic aglycones are nontoxic primers for glycosaminoglycan assembly in animal cells. However, when Ebselen was conjugated to d-xylose, d-glucose, d-galactose, and d-lactose (8A–D), only Ebselen β-d-xyloside (8A) showed significant cytotoxicity in human cancer cells. The following facts indicated that the aglycone Ebselen and β-d-xyloside primed glycosaminoglycans co-contributed to the observed cytotoxicity: 1. Ebselen induced S phase cell cycle arrest, whereas 8A induced G2/M cell cycle arrest; 2. 8A augmented early and late phase cancer cell apoptosis significantly compared to that of Ebselen and 8B–D; 3. Both 8A and phenyl-β-d-xyloside primed glycosaminoglycans with similar disaccharide compositions in CHO-pgsA745 cells; 4. Glycosaminoglycans could be detected inside of cells only when treated with 8A, indicating Ebselen contributed to the unique property of intracellular localization of the primed glycosaminoglycans. Thus, 8A represents a lead compound for the development of novel antitumor strategy by targeting glycosaminoglycans
Jianguo Fang - One of the best experts on this subject based on the ideXlab platform.
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Ebselen: A thioredoxin reductase-dependent catalyst for α-tocopherol quinone reduction
Toxicology and Applied Pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:Abstract The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if α-tocopherol quinone (TQ), a product of α-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, α-tocopherolhydroquinone (TQH 2 ), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.
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Ebselen: a thioredoxin reductase-dependent catalyst for alpha-tocopherol quinone reduction.
Toxicology and applied pharmacology, 2005Co-Authors: Jianguo Fang, Liangwei Zhong, Rong Zhao, Arne HolmgrenAbstract:The thioredoxin system, composed of thioredoxin (Trx), thioredoxin reductase (TrxR), and NADPH, is a powerful protein disulfide reductase system with a broad substrate specificity. Recently the selenazol drug Ebselen was shown to be a substrate for both mammalian TrxR and Trx. We examined if alpha-tocopherol quinone (TQ), a product of alpha-tocopherol oxidation, is reduced by Ebselen in the presence of TrxR, since TQ was not a substrate for the enzyme itself. Ebselen reduction of TQ in the presence of TrxR was caused by Ebselen selenol, generated from fast reduction of Ebselen by the enzyme. TQ has no intrinsic antioxidant activity, while the product of reduction of TQ, alpha-tocopherolhydroquinone (TQH(2)), is a potent antioxidant. The thioredoxin system dependence of Ebselen to catalyze reduction of other oxidized species, such as hydrogen peroxide, dehydroascorbate, and peroxynitrite, is discussed. The ability of Ebselen to reduce TQ via the thioredoxin system is a novel mechanism to explain the effects of the drug as an antioxidant in vivo.