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.
Toxicological responses to acetaminophen (APAP) overdose were evaluated in human hepatocytes transplanted chimeric mice using 2-dimensional gel electrophoresis (2DE)-based proteomics and (1)H-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.
Yamamoto
Toshinori
T
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories, Pfizer Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Toshinoro.Yamamoto@pfizer.com
Tomizawa
Kaori
K
Fujikawa
Masaaki
M
Sato
Yasushi
Y
Yamada
Hiroshi
H
Horii
Ikuo
I
D000082:Acetaminophen / Q000633:toxicity*; D000818:Animals; D001774:Blood Chemical Analysis; D002952:Citric Acid Cycle / Q000187:drug effects; D016000:Cluster Analysis; D015180:Electrophoresis, Gel, Two-Dimensional; D006019:Glycolysis / Q000187:drug effects; D022781:Hepatocytes / Q000637:transplantation*; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D023421:Models, Animal; D019906:Nuclear Magnetic Resonance, Biomolecular; D025341:Principal Component Analysis; D011506:Proteins / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D015203:Reproducibility of Results; D018675:Toxicity Tests / Q000379:methods*; D016482:Urinalysis; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*