Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context

Richard J. Wall, Guochun He, Michael S. Denison, Cenzo Congiu, Valentina Onnis, Alwyn Fernandes, David R. Bell, Martin Rose, J. Craig Rowlands, Gianfranco Balboni, Ian R. Mellor

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

The aryl hydrocarbon receptor (AhR) mediates the induction of a variety of xenobiotic metabolism genes. Activation of the AhR occurs through binding to a group of structurally diverse compounds, most notably dioxins, which are exogenous ligands. Isoflavones are part of a family which include some well characterised endogenous AhR ligands. This paper analysed a novel family of these compounds, based on the structure of 2-amino-isoflavone. Initially two luciferase-based cell models, mouse H1L6.1c2 and human HG2L6.1c3, were used to identify whether the compounds had AhR agonistic and/or antagonistic properties. This analysis showed that some of the compounds were weak agonists in mouse and antagonists in human. Further analysis of two of the compounds, Chr-13 and Chr-19, was conducted using quantitative real-time PCR in rat H4IIE and human MCF-7 cells. The results indicated that Chr-13 was an agonist in rat but an antagonist in human cells. Chr-19 was shown to be an agonist in rat but more interestingly, a partial agonist in human. Luciferase induction results not only revealed that subtle differences in the structure of the compound could produce species-specific differences in response but also dictated the ability of the compound to be an AhR agonist or antagonist. Substituted 2-amino-isoflavones represent a novel group of AhR ligands that must differentially interact with the AhR ligand binding domain to produce their species-specific agonist or antagonist activity and future ligand binding analysis and docking studies with these compounds may provide insights into the differential mechanisms of action of structurally similar compounds.

Original languageEnglish (US)
Pages (from-to)26-33
Number of pages8
JournalToxicology
Volume297
Issue number1-3
DOIs
StatePublished - Jul 16 2012

Keywords

  • Aryl hydrocarbon receptor (AhR)
  • Dioxin
  • Isoflavone
  • Species-specific

ASJC Scopus subject areas

  • Toxicology

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    Wall, R. J., He, G., Denison, M. S., Congiu, C., Onnis, V., Fernandes, A., Bell, D. R., Rose, M., Rowlands, J. C., Balboni, G., & Mellor, I. R. (2012). Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context. Toxicology, 297(1-3), 26-33. https://doi.org/10.1016/j.tox.2012.03.011