A mitochondria-targeted imidazole-substituted fatty acid inhibits cytochrome c peroxidase and mitigates radiation-induced death

Details

• Personal Author:
  Amoscato A ; Atkinson J ; Bayir H ; Belikova N ; Epperly M ; Feng W ; Fletcher J ; Greenberger J ; Huang Z ; Jiang J ; Kagan V ; Kapralov A ; Klein-Seetharaman J ; Maeda A ; Pearce L ; Peterson J ; Pitt B ; Samhan-Arias A ; Stoyanovsky D ; Tyurin V ; Tyurina Y ; Vlasova I ; Wang H ; Wang Y ; Yanamala N ; Amoscato A ; Atkinson J ; Bayir H ; Belikova N ; Epperly M ; Feng W ; Fletcher J ; Greenberger J ; Huang Z ; Jiang J ; Kagan V ; Kapralov A ; Klein-Seetharaman J ; Maeda A ; Pearce L ; Peterson J ; Pitt B ; Samhan-Arias A ; Stoyanovsky D ; Tyurin V ; Tyurina Y ; Vlasova I ; Wang H ; Wang Y ; Yanamala N
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Acids Cytology Cytotoxins Laboratories Occupational Health Radiation Radiation Injuries Radiation Protection Safety Stearates
• Keywords:
  Cell-alteration Cell-damage Cell-morphology Cellular-reactions Cytotoxic-effects Hemoproteins Imidazoles Ionizing-radiation Irradiation Laboratory-animals Lethal-dose Peroxidases Radiation-injury Radiation-protection Radiation-therapy Radioactive-fallout Radionuclides

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• ISSN:
  1096-6080
• Document Type:
  Text
• Funding:
  Grant
• Genre:
  Abstract or Summary ; Abstract or Summary
• Place as Subject:
  California ; OSHA Region 3 ; OSHA Region 9 ; Pennsylvania
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Volume:
  126
• NIOSHTIC Number:
  nn:20040660
• Citation:
  Toxicologist 2012 Mar; 126(Suppl 1):439
• CAS Registry Number:
  Stearic acid (CAS RN 57-11-4) ; Stearic acid (CAS RN 57-11-4)
• Federal Fiscal Year:
  2012
• NORA Priority Area:
  Manufacturing ; Manufacturing
• Performing Organization:
  University of Pittsburgh at Pittsburgh
• Peer Reviewed:
  False
• Start Date:
  20050701
• Source Full Name:
  The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
• Supplement:
  1
• End Date:
  20160630
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:b88a6d91d7f49bbbe4435861c4f37bab7fae04a0a70e9ce712e1f11c069b5b529fa7a4a6cef50aa40d390fde5af96f8438db0023c2720052ec1b3d879eb84125
• Download URL:
  https://stacks.cdc.gov/view/cdc/193450/cdc_193450_DS1.pdf
• File Type:
  [PDF - 467.74 KB ]