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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  • Igarashi Katsuhide
    Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
  • Kitajima Satoshi
    Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
  • Aisaki Ken-ichi
    Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences
  • 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 The Graduate University for Advanced Studies (Sokendai)
  • Blumberg Bruce
    Department of Developmental and Cell Biology, 2011 Biological Sciences 3, University of California
  • Kanno Jun
    Division of Cellular and Molecular Toxicology, Biological Safety Research Center, National Institute of Health Sciences

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Abstract

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.

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