Proteomic analysis of acetaminophen-induced hepatotoxicity and identification of heme oxygenase 1 as a potential plasma biomarker of liver injury.

Abstract

PURPOSE:

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.

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS AND CLINICAL RELEVANCE:

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: Yuan Gao, Zhijun Cao, Xi Yang, Mohamed A Abdelmegeed, Jinchun Sun, Si Chen, Richard D Beger, Kelly Davis, William F Salminen, Byoung-Joon Song, Donna L Mendrick, Li-Rong Yu
• Journal: Proteomics. Clinical applications (Proteomics Clin Appl) Vol. 11 Issue 1-2 (01 2017) ISSN: 1862-8354 [Electronic] Germany
• PMID: 27634590 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Chemical References

• Biomarkers
• Oxygen Isotopes
• Acetaminophen
• Heme Oxygenase-1
• Oxidoreductases Acting on CH-CH Group Donors
• biliverdin reductase
• Aspartate Aminotransferases
• Alanine Transaminase

Topics

• Acetaminophen (toxicity)
• Alanine Transaminase (blood)
• Animals
• Aspartate Aminotransferases (blood)
• Biomarkers (analysis)
• Chemical and Drug Induced Liver Injury (etiology, metabolism, pathology)
• Chromatography, High Pressure Liquid
• Electrophoresis, Gel, Two-Dimensional
• Enzyme-Linked Immunosorbent Assay
• Heme Oxygenase-1 (analysis, blood, metabolism)
• Isotope Labeling
• Liver (drug effects, metabolism, pathology)
• Male
• Oxidoreductases Acting on CH-CH Group Donors (analysis, metabolism)
• Oxygen Isotopes (chemistry)
• Proteomics
• Rats
• Rats, Sprague-Dawley
• Tandem Mass Spectrometry