title: Identification of Organ-Enriched Protein Biomarkers of Acute Liver Injury by Targeted Quantitative Proteomics of Blood in Acetaminophen- and Carbon-Tetrachloride-Treated Mouse Models and Acetaminophen Overdose Patients.
abstract: Organ-enriched blood proteins, those produced primarily in one organ and secreted or exported to the blood, potentially afford a powerful and specific approach to assessing diseases in their cognate organs. We demonstrate that quantification of organ-enriched proteins in the blood offers a new strategy to find biomarkers for diagnosis and assessment of drug-induced liver injury (and presumably the assessment of other liver diseases). We used selected reaction monitoring (SRM) mass spectrometry to quantify 81 liver-enriched proteins plus three aminotransferases (ALT1, AST1, and AST2) in plasma of C57BL/6J and NOD/ShiLtJ mice exposed to acetaminophen or carbon tetrachloride. Plasma concentrations of 49 liver-enriched proteins were perturbed significantly in response to liver injury induced by one or both toxins. We validated four of these toxin-responsive proteins (ALDOB, ASS1, BHMT, and GLUD1) by Western blotting. By both assays, these four proteins constitute liver injury markers superior to currently employed markers such as ALT and AST. A similar approach was also successful in human serum where we had analyzed 66 liver-enriched proteins in acetaminophen overdose patients. Of these, 23 proteins were elevated in patients; 15 of 23 overlapped with the concentration-increased proteins in the mouse study. A combination of 5 human proteins, AGXT, ALDOB, CRP, FBP1, and MMP9, provides the best diagnostic performance to distinguish acetaminophen overdose patients from controls (sensitivity: 0.85, specificity: 0.84, accuracy: 85%). These five blood proteins are candidates for detecting acetaminophen-induced liver injury using next-generation diagnostic devices (e.g, microfluidic ELISA assays).
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Shizhen
authors: S
authors: Qin
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Yong
authors: Y
authors: Zhou
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Li
authors: L
authors: Gray
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Ulrike
authors: U
authors: Kusebauch
authors: Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.
authors: Laurence
authors: L
authors: McEvoy
authors: Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.
authors: Daniel J
authors: DJ
authors: Antoine
authors: Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.
authors: Lucy
authors: L
authors: Hampson
authors: Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.
authors: Kevin B
authors: KB
authors: Park
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: David
authors: D
authors: Campbell
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Juan
authors: J
authors: Caballero
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Gustavo
authors: G
authors: Glusman
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Xiaowei
authors: X
authors: Yan
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Taek-Kyun
authors: TK
authors: Kim
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Yue
authors: Y
authors: Yuan
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Kai
authors: K
authors: Wang
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Lee
authors: L
authors: Rowen
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Robert L
authors: RL
authors: Moritz
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.|Departments of Computational Medicine & Bioinformatics, Internal Medicine, and Human Genetics and School of Public Health, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, United States.
authors: Gilbert S
authors: GS
authors: Omenn
authors: Institute of Translational Medicine at University of Liverpool , 1-5 Brownlow Street, Liverpool L69 3GL, England.
authors: Munir
authors: M
authors: Pirmohamed
authors: Institute for Systems Biology , 401 Terry North, Seattle, Washington 98109-5234, United States.
authors: Leroy
authors: L
authors: Hood
mesh_terms: D000082:Acetaminophen / Q000008:administration & dosage / Q000633:toxicity*; D000328:Adult; D000368:Aged; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001774:Blood Chemical Analysis; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis*; D062787:Drug Overdose / Q000175:diagnosis; D006801:Humans; D051379:Mice; D008875:Middle Aged; D040901:Proteomics / Q000379:methods*
chemical_list: D015415:Biomarkers; D000082:Acetaminophen; D002251:Carbon Tetrachloride
keywords: acetaminophen; biomarker panel; drug-induced liver injury; liver-enriched proteins; selected reaction monitoring