title: Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury.
abstract: Overdose of acetaminophen (APAP) is a major cause of acute liver failure. This study was aimed to identify pathways related to hepatotoxicity and potential biomarkers of liver injury.
  
  
  
  Rats were treated with low (100 mg/kg) and high (1250 mg/kg) doses of APAP, and liver tissues at 6 and 24 h post-treatment were analyzed using a proteomic approach of 16O/18O labeling and 2D-LC-MS/MS.
  
  
  
  Molecular pathways evolved progressively from scattered and less significant perturbations to more focused and significant alterations in a dose- and time-dependent manner upon APAP treatment. Imbalanced expression of hemeoxygenase 1 (HMOX1) and biliverdin reductase A (BLVRA) was associated with hepatotoxicity. Protein abundance changes of a total of 31 proteins were uniquely correlated to liver damage, among which a dramatic increase of HMOX1 levels in plasma was observed. Liver injury-associated significant elevation of plasma HMOX1 was further validated in mice treated with APAP.
  
  
  
  This study unveiled molecular changes associated with APAP-induced liver toxicity at the pathway levels and identified HMOX1 as a potential plasma biomarker of liver injury.
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Jinchun
authors.initials: J
authors.lastname: Sun
authors.affiliation: Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Si
authors.initials: S
authors.lastname: Chen
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Beger
authors.affiliation: Toxicologic Pathology Associates, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Davis
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: William F
authors.initials: WF
authors.lastname: Salminen
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Donna L
authors.initials: DL
authors.lastname: Mendrick
authors.affiliation: Division of Systems Biology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA.
authors.forename: Li-Rong
authors.initials: LR
authors.lastname: Yu
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D015415:Biomarkers / Q000032:analysis*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D002851:Chromatography, High Pressure Liquid; D015180:Electrophoresis, Gel, Two-Dimensional; D004797:Enzyme-Linked Immunosorbent Assay; D051547:Heme Oxygenase-1 / Q000032:analysis* / Q000097:blood / Q000378:metabolism; D007553:Isotope Labeling; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000032:analysis / Q000378:metabolism; D010103:Oxygen Isotopes / Q000737:chemistry; D040901:Proteomics; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry
chemical_list: D015415:Biomarkers; D010103:Oxygen Isotopes; D000082:Acetaminophen; D051547:Heme Oxygenase-1; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019789:biliverdin reductase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Acetaminophen; Heme oxygenase 1 (HMOX1); Hepatotoxicity; MS