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A mitochondria-targeted imidazole-substituted fatty acid inhibits cytochrome c peroxidase and mitigates radiation-induced death.
Atkinson-J; Kapralov-A; Yanamala-N; Tyurina-Y; Amoscato-A; Pearce-L; Peterson-J; Huang-Z; Jiang-J; Samhan-Arias-A; Maeda-A; Feng-W; Belikova-N; Tyurin-V; Wang-H; Fletcher-J; Wang-Y; Vlasova-I; Klein-Seetharaman-J; Stoyanovsky-D; Bayir-H; Pitt-B; Epperly-M; Greenberger-J; Kagan-V
Toxicologist 2012 Mar; 126(Suppl 1):439
The risk of radionuclide release in terrorist acts or exposure of healthy tissue during radiotherapy demand novel potent radioprotectants. Ionizing radiation induces cell death by initiating the selective peroxidation of cardiolipin (CL) in mitochondria by the peroxidase activity of its complex with cytochrome c leading to release of hemoprotein into the cytosol and commitment to the apoptotic program. We designed and synthesized mitochondria-targeted triphenylphosphonium-conjugated imidazole-substituted oleic (TPP-OA) and stearic (TPP-SA) acids. We found that TPP-IOA and TPP-ISA exerted strong specific liganding of heme-iron in cyt c/CL complex, effectively suppressed its peroxidase activity and CL peroxidation. In addition, TPP-IOA and TPP-ISA prevented cell death induced by irradiation. Both TPP-IOA and TPP-ISA protected/mitigated C57BL6 mice against lethal doses of irradiation. Significant radioprotective/radiomitigative effects of TPP-OA were observed after pretreatment of mice from 1 h before through 24 h after irradiation. This is an important advance in the development of radioprotectors with broad spectrum of applications in biomedicine and biodefense.
Radiation; Radiation-injury; Radionuclides; Radioactive-fallout; Radiation-therapy; Radiation-protection; Ionizing-radiation; Cell-alteration; Cell-damage; Cell-morphology; Cellular-reactions; Peroxidases; Cytology; Cytotoxic-effects; Hemoproteins; Acids; Stearates; Irradiation; Laboratory-animals; Lethal-dose; Imidazoles
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
University of Pittsburgh at Pittsburgh