title: Design and Synthesis of a Mitochondria-Targeted Mimic of Glutathione Peroxidase, MitoEbselen-2, as a Radiation Mitigator.
abstract: Ionizing radiation (IR) triggers mitochondrial overproduction of H2O2and accumulation of lipid hydroperoxides leading to the induction of apoptotic and necroptotic cell death pathways. Given the high catalytic efficiency of the seleno-enzyme glutathione peroxidase (Gpx) toward reduction of lipid hydroperoxides and H2O2, we tested the potential of mitochondria-targeted derivatives of ebselen to mitigate the deleterious effects of IR. We report that 2-[[2-[4-(3-oxo-1,2-benzoselenazol-2-yl)phenyl]acetyl]amino]ethyl-triphenyl-phosphonium chloride (MitoPeroxidase 2) was effective in reducing lipid hydroperoxides, preventing apoptotic cell death, and, when administered 24 h postirradiation, increased the survival of mice exposed to whole body γ-irradiation.
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Detcho A
authors.initials: DA
authors.lastname: Stoyanovsky
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Jianfei
authors.initials: J
authors.lastname: Jiang
authors.affiliation: Medical Research Council Mitochondrial Biology Unit , Wellcome Trust/MRC Building, Hills Road, Cambridge, U.K.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Epperly
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Xiaolan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Song
authors.initials: S
authors.lastname: Li
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Greenberger
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Valerian
authors.initials: V
authors.lastname: Kagan
authors.affiliation: Departments of Environmental and Occupational Health, Critical Care Medicine, Radiation Oncology, and Pharmaceutical Sciences, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
authors.forename: Hülya
authors.initials: H
authors.lastname: Bayır
keywords: Ebselen; H2O2; apoptosis; mitigators; mitochondria; radiation