Blockade of the Dioxin Pathway by Herbal Medicine Formula Bupleuri Minor: Identification of Active Entities for Suppression of AhR Activation

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  • Kasai Ayumi
    Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi
  • Hiramatsu Nobuhiko
    Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi
  • Hayakawa Kunihiro
    Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi
  • Yao Jian
    Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi
  • Kitamura Masanori
    Department of Molecular Signaling, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi

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Environmental pollutants including dioxins activate the aryl hydrocarbon receptor (AhR) and cause a wide range of pathologies. Development of AhR antagonists will be useful for prevention and treatment of the diseases related to AhR activation. Towards this goal, we aimed at seeking for potential AhR antagonists in herbal medicines using the dioxin responsive element-based sensing via secreted alkaline phosphatase (DRESSA). Through initial rough screening, 4 formulae were selected from 20 herbal medicines and subjected to the second, detailed screening. We found that only Formula bupleuri minor (TJ-9) significantly inhibited activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Among 7 raw herb extracts in TJ-9, Glycyrrhizae Radix and Scutellariae Radix were responsible for the antagonistic effect of TJ-9 against dioxin. Some constituents including Bupleuri Radix and Zingiberis Rhizoma rather activated AhR. Among 12 major constituents of Glycyrrhizae Radix and Scutellariae Radix, we identified that licopyranocoumarin, glycyrrhizic acid and genistein in Glycyrrhizae Radix and baicalein, wogonin and daidzein in Scutellariae Radix had substantial antagonistic effects on AhR. Among these, baicalein most effectively blocked activation of AhR triggered by cigarette smoke, a strong activator of AhR. The antagonistic substances identified here may be useful for prevention from diseases associated with aberrant activation of AhR.

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