The Journal of Toxicological Sciences
Online ISSN : 1880-3989
Print ISSN : 0388-1350
Original Article
EVALUATION OF HUMAN HEPATOCYTE CHIMERIC MICE AS A MODEL FOR TOXICOLOGICAL INVESTIGATION USING PANOMIC APPROACHES - EFFECT OF ACETAMINOPHEN ON THE EXPRESSION PROFILES OF PROTEINS AND ENDOGENOUS METABOLITES IN LIVER, PLASMA AND URINE
Toshinori YAMAMOTOKaori TOMIZAWAMasaaki FUJIKAWAYasushi SATOHiroshi YAMADAIkuo HORII
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Volume 32 (2007) Issue 3 Pages 205-215

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Abstract

Toxicological responses to acetaminophen (APAP) overdose were evaluated in human hepatocytes transplanted chimeric mice using 2-dimensional gel electrophoresis (2DE)-based proteomics and 1H-nuclear magnetic resonance (NMR)-based metabonomics. Huge variations, which were supported by histopathological findings, were observed in proteins expression in chimeric mice liver. The proteomic analysis of the livers showed that the proteins involved in the pathways of lipid/fatty acid metabolism, glycolysis and energy metabolism/production were affected. In addition, oxidative stress-related proteins showed altered expression. The metabonomic analysis of urine and plasma revealed alterations of endogenous metabolites, which were the intermediates involved in the tricarboxylic acid (TCA) cycle. Those findings were already confirmed in normal mice. We hypothesized that the mechanism of APAP-induced effects on chimeric mice liver was in accordance with the mechanism observed in normal mice. Therefore, these toxicopanomic approaches successfully revealed that the mechanisms in humans were identical with "known" APAP-induced hepatotoxicity detected in chimeric mice. Further investigations are needed to detect idiosyncratic hepatotoxicity in humans using chimeric mice.

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© 2007 The Japanese Society of Toxicology
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