title: Integrative Metabolic Signatures for Hepatic Radiation Injury.
abstract: BACKGROUND
  Radiation-induced liver disease (RILD) is a dose-limiting factor in curative radiation therapy (RT) for liver cancers, making early detection of radiation-associated liver injury absolutely essential for medical intervention. A metabolomic approach was used to determine metabolic signatures that could serve as biomarkers for early detection of RILD in mice.
  
  
  METHODS
  Anesthetized C57BL/6 mice received 0, 10 or 50 Gy Whole Liver Irradiation (WLI) and were contrasted to mice, which received 10 Gy whole body irradiation (WBI). Liver and plasma samples were collected at 24 hours after irradiation. The samples were processed using Gas Chromatography/Mass Spectrometry and Liquid Chromatography/Mass Spectrometry.
  
  
  RESULTS
  Twenty four hours after WLI, 407 metabolites were detected in liver samples while 347 metabolites were detected in plasma. Plasma metabolites associated with 50 Gy WLI included several amino acids, purine and pyrimidine metabolites, microbial metabolites, and most prominently bradykinin and 3-indoxyl-sulfate. Liver metabolites associated with 50 Gy WLI included pentose phosphate, purine, and pyrimidine metabolites in liver. Plasma biomarkers in common between WLI and WBI were enriched in microbial metabolites such as 3 indoxyl sulfate, indole-3-lactic acid, phenyllactic acid, pipecolic acid, hippuric acid, and markers of DNA damage such as 2-deoxyuridine. Metabolites associated with tryptophan and indoles may reflect radiation-induced gut microbiome effects. Predominant liver biomarkers in common between WBI and WLI were amino acids, sugars, TCA metabolites (fumarate), fatty acids (lineolate, n-hexadecanoic acid) and DNA damage markers (uridine).
  
  
  CONCLUSIONS
  We identified a set of metabolomic markers that may prove useful as plasma biomarkers of RILD and WBI. Pathway analysis also suggested that the unique metabolic changes observed after liver irradiation was an integrative response of the intestine, liver and kidney.
authors.affiliation: Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Irwin Jack
authors.initials: IJ
authors.lastname: Kurland
authors.affiliation: Division of Computational Genetics, Genetics Department, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Pilib Ó
authors.initials: PÓ
authors.lastname: Broin
authors.affiliation: Division of Computational Genetics, Genetics Department, Albert Einstein College of Medicine, Bronx, New York, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Golden
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Gang
authors.initials: G
authors.lastname: Su
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, Michigan, United States of America.
authors.forename: Fan
authors.initials: F
authors.lastname: Meng
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, Unites States of America.
authors.forename: Laibin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Metabolon, Durham, North Carolina, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Mohney
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, Unites States of America.
authors.forename: Shilpa
authors.initials: S
authors.lastname: Kulkarni
authors.affiliation: Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, New York, Unites States of America.
authors.forename: Chandan
authors.initials: C
authors.lastname: Guha
mesh_terms: D000596:Amino Acids / Q000032:analysis / Q000097:blood; D000818:Animals; D015415:Biomarkers / Q000032:analysis / Q000097:blood*; D002851:Chromatography, High Pressure Liquid; D016002:Discriminant Analysis; D008401:Gas Chromatography-Mass Spectrometry; D008099:Liver / Q000378:metabolism* / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D025341:Principal Component Analysis; D011832:Radiation Injuries; D053719:Tandem Mass Spectrometry; D014916:Whole-Body Irradiation
chemical_list: D000596:Amino Acids; D015415:Biomarkers