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.
J Proteome Res
; 15(10): 3724-3740, 2016 10 07.
Article
em En
| MEDLINE
| ID: mdl-27575953
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).
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteômica
/
Doença Hepática Induzida por Substâncias e Drogas
/
Acetaminofen
Tipo de estudo:
Diagnostic_studies
/
Prognostic_studies
Limite:
Adult
/
Aged
/
Animals
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Humans
/
Middle aged
Idioma:
En
Revista:
J Proteome Res
Assunto da revista:
BIOQUIMICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Estados Unidos