title: Superoxide mediates acute liver injury in irradiated mice lacking sirtuin 3.
abstract: OBJECTIVE
  This study determined whether acute radiation-induced liver injury seen in Sirtuin3(-/-) mice after exposure to Cs-137 γ-rays was mediated by superoxide anion (O2(•-)).
  
  
  RESULTS
  Male wild-type (WT) and SIRT3(-/-) mice were given 2×2 Gy whole-body radiation doses separated by 24 h and livers were harvested 20 h after the second dose. Ex vivo measurements in fresh frozen liver sections demonstrated 50% increases in dihydroethidium oxidation from SIRT3(-/-) animals, relative to WT animals, before irradiation, but this increase was not detected 20 h after radiation exposure. In addition, irradiated livers from SIRT3(-/-) animals showed significant hydropic degeneration, loss of MitoTracker Green FM staining, increased immunohistochemical staining for 3-nitrotyrosine, loss of Ki67 staining, and increased mitochondrial localization of p53. These parameters of radiation-induced injury were significantly attenuated by an intraperitoneal injection of 2 mg/kg of the highly specific superoxide dismutase mimic, GC4401, 30 min before each fraction.
  
  
  METHODS
  Sirtuin 3 (SIRT3) is believed to regulate mitochondrial oxidative metabolism and antioxidant defenses in response to acute radiation-induced liver injury. This work provides strong evidence for the causal role of O2(•-) in the liver injury process initiated by whole-body irradiation in SIRT3(-/-) mice.
  
  
  CONCLUSIONS
  These results support the hypothesis that O2(•-) mediates acute liver injury in SIRT3(-/-) animals exposed to whole-body γ-radiation and suggest that GC4401 could be used as a radio-protective compound in vivo.
authors.affiliation: 1 Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Carver College of Medicine, The University of Iowa , Iowa City, Iowa.
authors.forename: Mitchell C
authors.initials: MC
authors.lastname: Coleman
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Olivier
authors.forename: James A
authors.initials: JA
authors.lastname: Jacobus
authors.forename: Kranti A
authors.initials: KA
authors.lastname: Mapuskar
authors.forename: Gaowei
authors.initials: G
authors.lastname: Mao
authors.forename: Sean M
authors.initials: SM
authors.lastname: Martin
authors.forename: Dennis P
authors.initials: DP
authors.lastname: Riley
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Spitz
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004579:Electron Transport / Q000528:radiation effects; D004789:Enzyme Activation; D004996:Ethidium / Q000031:analogs & derivatives / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D010084:Oxidation-Reduction; D021381:Protein Transport; D056566:Sirtuin 3 / Q000172:deficiency*; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014916:Whole-Body Irradiation
chemical_list: D016159:Tumor Suppressor Protein p53; C067883:dihydroethidium; D013481:Superoxides; D013482:Superoxide Dismutase; D056566:Sirtuin 3; D004996:Ethidium
references.citation: Nature. 2010 Mar 4;464(7285):121-5
references.pmid: 20203611
references.citation: Cancer Res. 2005 May 1;65(9):3745-50
references.pmid: 15867370
references.citation: PLoS One. 2010 May 05;5(5):e10486
references.pmid: 20463968
references.citation: Cell Metab. 2010 Dec 1;12(6):654-61
references.pmid: 21109197
references.citation: Am J Physiol Lung Cell Mol Physiol. 2000 Apr;278(4):L719-25
references.pmid: 10749749
references.citation: Mol Cell Biol. 2003 Apr;23(7):2362-78
references.pmid: 12640121
references.citation: Mol Cell Biol. 2008 Oct;28(20):6384-401
references.pmid: 18710944
references.citation: Science. 1999 Oct 8;286(5438):304-6
references.pmid: 10514375
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14447-52
references.pmid: 18794531
references.citation: J Biol Chem. 1998 Nov 20;273(47):30961-72
references.pmid: 9812992
references.citation: Cell Mol Biol (Noisy-le-grand). 2000 May;46(3):657-62
references.pmid: 10872752
references.citation: Mol Cell. 2010 Dec 22;40(6):893-904
references.pmid: 21172655
references.citation: J Cardiovasc Pharmacol. 1998 Sep;32(3):343-8
references.pmid: 9733345
references.citation: Free Radic Biol Med. 2001 Nov 1;31(9):1101-10
references.pmid: 11677043
references.citation: Physiol Rev. 1979 Jul;59(3):527-605
references.pmid: 37532
references.citation: Biochem Med Metab Biol. 1994 Feb;51(1):35-42
references.pmid: 8192914
references.citation: Nat Protoc. 2008;3(6):941-7
references.pmid: 18536642
references.citation: Inorg Chem. 2001 Apr 9;40(8):1779-89
references.pmid: 11312732
references.citation: Int J Biol Sci. 2008 Sep 05;4(5):291-9
references.pmid: 18781224
references.citation: Free Radic Res. 2010 May;44(5):529-40
references.pmid: 20298121
references.citation: Ann N Y Acad Sci. 2010 Jul;1201:129-36
references.pmid: 20649549
references.citation: Cancer Cell. 2010 Jan 19;17(1):41-52
references.pmid: 20129246
references.citation: Radiat Res. 2000 Oct;154(4):365-74
references.pmid: 11023599
references.citation: Free Radic Biol Med. 2002 Jan 15;32(2):175-86
references.pmid: 11796207
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Apr;294(4):R1165-74
references.pmid: 18272664
references.citation: Circ Res. 2010 Jul 9;107(1):106-16
references.pmid: 20448215
references.citation: PLoS One. 2010 Jul 30;5(7):e11902
references.pmid: 20689586
references.citation: J Sports Sci. 2009 Jan 1;27(1):49-58
references.pmid: 19031335
references.citation: Int J Radiat Biol Relat Stud Phys Chem Med. 1976 Mar;29(3):297-9
references.pmid: 1083851
references.citation: Cancer Biol Ther. 2008 Aug;7(8):1271-9
references.pmid: 18497575
references.citation: Antioxid Redox Signal. 2006 Jul-Aug;8(7-8):1273-81
references.pmid: 16910775
references.citation: Radiat Res. 2009 Dec;172(6):737-45
references.pmid: 19929420
references.citation: Oncogene. 2006 Mar 9;25(10):1554-9
references.pmid: 16261162
references.citation: Aging (Albany NY). 2010 Dec;2(12):914-23
references.pmid: 21212461
references.citation: Free Radic Biol Med. 1999 Jun;26(11-12):1447-56
references.pmid: 10401608
references.citation: Hypertension. 2007 Apr;49(4):717-27
references.pmid: 17296874
references.citation: Aging Cell. 2008 Jun;7(3):405-17
references.pmid: 18331617
references.citation: J Radiat Res. 2012;53(1):58-71
references.pmid: 22302046
references.citation: J Biol Chem. 2005 May 6;280(18):18033-41
references.pmid: 15743756
references.citation: Annu Rev Biochem. 1995;64:97-112
references.pmid: 7574505
references.citation: Cancer Res. 2006 Aug 1;66(15):7615-20
references.pmid: 16885361
references.citation: Anal Biochem. 1989 May 15;179(1):8-18
references.pmid: 2547324