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Research ArticleArticle

Acetaminophen-Induced Hepatotoxicity in a Liver Tissue Model Consisting of Primary Hepatocytes Assembling around an Endothelial Cell Network

Yu Toyoda, Miho Tamai, Kasumi Kashikura, Shunsuke Kobayashi, Yoichi Fujiyama, Tomoyoshi Soga and Yoh-ichi Tagawa
Drug Metabolism and Disposition January 2012, 40 (1) 169-177; DOI: https://doi.org/10.1124/dmd.111.041137
Yu Toyoda
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Miho Tamai
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Kasumi Kashikura
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Shunsuke Kobayashi
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Yoichi Fujiyama
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Tomoyoshi Soga
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Yoh-ichi Tagawa
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Abstract

Primary hepatocytes have been used in drug development for the evaluation of hepatotoxicity of candidate compounds. However, the rapid depression of their hepatic characters in vitro must be improved to predict toxicity with higher accuracy. We have hypothesized that a well organized tissue construct that includes nonparenchymal cells and appropriate scaffold material(s) could overcome this difficulty by remediating the viability and physiological function of primary hepatocytes. In this study, we constructed an in vitro liver tissue model, consisting of mouse primary hepatocytes assembling around an endothelial cell network on Engelbreth-Holm-Swarm gel, and examined its response to acetaminophen treatment. The increase in lactate dehydrogenase release after the exposure to acetaminophen was induced earlier in the liver tissue model than in monolayer hepatocytes alone, suggesting that the tissue model was more sensitive to an acetaminophen-induced toxicity. On the basis of our results, we conclude that liver tissue models of this kind may enhance the responses of hepatocytes against xenobiotics via the maintenance of hepatic genes and functions such as cytochrome P450s. These findings will contribute to the development of more accurate systems for evaluating hepatotoxicity.

Footnotes

  • This work was supported by the Precursory Research for Embryonic Science and Technology and the Adaptable and Seamless Technology transfer Program through target-driven R&D funding [Grant AS2211513G] from the Japan Science and Technology Agency (JST); a Grant-in-Aid for Scientific Research (B) [Grant 21300178] from the Japanese Society for the Promotion of Science (JSPS); and a Grant-in-Aid for Scientific Research on Innovative Areas [Grant 23119003] from the Ministry of Education, Culture, Sports, Science and Technology. Y.To. and M.T. are JSPS research fellows.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.111.041137.

  • ABBREVIATIONS:

    ECM
    extracellular matrix
    ES
    embryonic stem
    IVLmES
    mouse ES cell-derived in vitro liver tissue model
    HUVEC
    human umbilical vein endothelial cell
    NAPQI
    N-acetyl-p-benzoquinone imine
    IVL
    in vitro liver model
    APAP
    N-(4-hydroxyphenyl)acetamide
    EHS
    Engelbreth-Holm-Swarm
    OHT
    hydroxytestosterone
    HP
    hydroxyprogesterone
    EGM-2
    endothelial cell growth medium-2
    DMEM
    Dulbecco's modified Eagle's medium
    HBSS
    Hank's balanced salt solution
    LDH
    lactate dehydrogenase
    HPLC
    high-performance liquid chromatography
    CE-TOFMS
    capillary electrophoresis coupled with electrospray ionization time-of-flight mass spectrometry
    PECAM-1
    platelet endothelial cell adhesion molecule-1
    vWF
    Von Willebrand factor
    HGF
    hepatocyte growth factor
    IVLEHS
    in vitro liver model on EHS gel
    RT-PCR
    reverse transcription-polymerase chain reaction
    hprt
    hypoxanthine-guanine phosphoribosyltransferase
    TAT
    tyrosine aminotransferase.

  • Received June 10, 2011.
  • Accepted October 18, 2011.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (1)
Drug Metabolism and Disposition
Vol. 40, Issue 1
1 Jan 2012
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Research ArticleArticle

NOVEL ASSAY SYSTEM FOR HEPATOTOXICITY: LIVER TISSUE MODEL

Yu Toyoda, Miho Tamai, Kasumi Kashikura, Shunsuke Kobayashi, Yoichi Fujiyama, Tomoyoshi Soga and Yoh-ichi Tagawa
Drug Metabolism and Disposition January 1, 2012, 40 (1) 169-177; DOI: https://doi.org/10.1124/dmd.111.041137

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Research ArticleArticle

NOVEL ASSAY SYSTEM FOR HEPATOTOXICITY: LIVER TISSUE MODEL

Yu Toyoda, Miho Tamai, Kasumi Kashikura, Shunsuke Kobayashi, Yoichi Fujiyama, Tomoyoshi Soga and Yoh-ichi Tagawa
Drug Metabolism and Disposition January 1, 2012, 40 (1) 169-177; DOI: https://doi.org/10.1124/dmd.111.041137
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