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
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概要
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Toxicological responses to acetaminophen (APAP) overdose were evaluated in human hepatocytes transplanted chimeric mice using 2-dimensional gel electrophoresis (2DE)-based proteomics and '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.
- 日本トキシコロジー学会の論文
- 2007-08-17
著者
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HORII IKUO
Drug Safety Evaluation, Nagoya Laboratories, Pfizer Global Research and Development
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Yamamoto Toshinori
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Yamamoto T
Showa Univ. Tokyo Jpn
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Yamamoto Toshinori
Department Of Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Horii Ikuo
Showa Univ. (department Of Biochemical Toxicology School Of Pharmaceutical Sciences)
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Horii I
Drug Safety Research And Development Pfizer Global Research And Development Nagoya Laboratories. Pfi
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Horii Ikuo
Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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YAMADA Hiroshi
Drug Safety Research and Development, Nagoya Laboratories, Pfizer Japan Inc.
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TOMIZAWA Kaori
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories
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FUJIKAWA Masaaki
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories
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SATO Yasushi
Drug Safety Research & Development, Pfizer Global Research & Development, Nagoya Laboratories
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Tomizawa Kaori
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Yamada Hiroshi
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Horii Ikuo
Worldwide Safety Sciences Pgrd Nagoya Laboratories Pfizer Inc.
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Fujikawa Masaaki
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Fujikawa Masaaki
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Japan
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Yamamoto Toshinori
Departments Of Clinical Pharmacy And Pharmacognosy School Of Pharmaceutical Sciences Showa Universit
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Horii Ikuo
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Inc.
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Yamamoto Toshinori
Drug Metabolism Laboratory Chugai Pharmaceutical Co. Ltd.
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Horii Ikuo
Drug Safety Evaluation Pfizer Global Research And Development
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Fujikawa Masaaki
Worldwide Safety Sciences Pfizer Global Research & Development Nagoya Laboratories Pfizer Japan
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Horii Ikuo
Drug Safety Evaluation Global Research & Development Pfizer Inc.
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Horii Ikuo
Biochemical Toxicology School Of Pharmaceutical Sciences Showa University
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Sato Yasushi
Drug Safety Research & Development Pfizer Global Research & Development Nagoya Laboratories
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Yamada Hiroshi
Worldwide Safety Sciences Pfizer Global Research And Development Nagoya Laboratories Pfizer Japan In
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Yamamoto Toshinori
Department Of Pharmacology Medical College Of Oita
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Sato Yasushi
Drug Safety And Pharmacokinetics Laboratories Taisho Pharmaceutical Co. Ltd.
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