Development of humanized steroid and xenobiotic receptor mouse by homologous knock-in of the human steroid and xenobiotic receptor ligand binding domain sequence

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著者

    • TANEMURA Kentaro
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
    • TAQUAHASHI Yuhji
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
    • MORIYAMA Noriko
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
    • IKENO Eriko
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
    • MATSUDA Nae
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
    • SAGA Yumiko
    • Division of Mammalian Development, National Institute of Genetics
    • KANNO Jun
    • Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences

抄録

The human steroid and xenobiotic receptor (SXR), (also known as pregnane X receptor PXR, and NR1I2) is a low affinity sensor that responds to a variety of endobiotic, nutritional and xenobiotic ligands. SXR activates transcription of Cytochrome P450, family 3, subfamily A (CYP3A) and other important metabolic enzymes to up-regulate catabolic pathways mediating xenobiotic elimination. One key feature that demarcates SXR from other nuclear receptors is that the human and rodent orthologues exhibit different ligand preference for a subset of toxicologically important chemicals. This difference leads to a profound problem for rodent studies to predict toxicity in humans. The objective of this study is to generate a new humanized mouse line, which responds systemically to human-specific ligands in order to better predict systemic toxicity in humans. For this purpose, the ligand binding domain (LBD) of the human SXR was homologously knocked-in to the murine gene replacing the endogenous LBD. The LBD-humanized chimeric gene was expressed in all ten organs examined, including liver, small intestine, stomach, kidney and lung in a pattern similar to the endogenous gene expressed in the wild-type (WT) mouse. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the human-selective ligand, rifampicin induced Cyp3a11 and Carboxylesterase 6 (Ces6) mRNA expression in liver and intestine, whereas the murine-selective ligand, pregnenolone-16-carbonitrile did not. This new humanized mouse line should provide a useful tool for assessing whole body toxicity, whether acute, chronic or developmental, induced by human selective ligands themselves and subsequently generated metabolites that can trigger further toxic responses mediated secondarily by other receptors distributed body-wide.

収録刊行物

  • Journal of toxicological sciences

    Journal of toxicological sciences 37(2), 373-380, 2012-04-01

    The Japanese Society of Toxicology

参考文献:  19件中 1-19件 を表示

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各種コード

  • NII論文ID(NAID)
    10030126875
  • NII書誌ID(NCID)
    AN00002808
  • 本文言語コード
    ENG
  • 資料種別
    ART
  • ISSN
    03881350
  • NDL 記事登録ID
    023674648
  • NDL 請求記号
    Z19-1022
  • データ提供元
    CJP書誌  CJP引用  NDL  J-STAGE 
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