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LC‐MS‐based metabolomics of acetaminophen‐induced acute toxicity
Author(s) -
Chen Chi,
Krausz Kristopher W,
Shah Yatrik M,
Idle Jeffrey R,
Gonzalez Frank J
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.760.4
Subject(s) - metabolomics , cyp2e1 , acetaminophen , pharmacology , toxicity , chemistry , aspartate transaminase , acute toxicity , liver injury , alanine transaminase , chromatography , medicine , biochemistry , cytochrome p450 , metabolism , enzyme , alkaline phosphatase , organic chemistry
Acetaminophen (APAP)‐induced acute toxicity is a clinically important model for studying drug‐induced liver injury. In order to discover potential biomarkers of APAP‐induced toxicity, a LC‐MS‐based metabolomic study was conducted to investigate the differential response from wildtype and cyp2e1‐null mice to APAP overdose. Serum samples collected during APAP treatment were analyzed by an UPLC‐QTOF LC‐MS system. Chromatograms and mass spectra were deconvoluted into a data matrix for multivariate data analysis. Results from these analyses revealed the correlation between hepatotoxicity and metabolomic profiles of serum samples since APAP treatment led to a far greater changes in the metabolomic profile of wild‐type mice than that of cyp2e1‐null mice in the multivariate model. Among the group of serum ions contributing this observation, several acylcarnitines including pamitoylcarnitine and myristoylcarnitine are very prominent because of their parallel increase with transaminase activity and their role in fatty acid beta‐oxidation. Overall, the combination of genetically‐modified animal models and metabolomics provide a powerful tool to characterize APAP‐induced liver toxicity and undercover novel mechanism.