title: Novel 2-amino-isoflavones exhibit aryl hydrocarbon receptor agonist or antagonist activity in a species/cell-specific context.
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.
authors.affiliation: School of Biology, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wall
authors.forename: Guochun
authors.initials: G
authors.lastname: He
authors.forename: Michael S
authors.initials: MS
authors.lastname: Denison
authors.forename: Cenzo
authors.initials: C
authors.lastname: Congiu
authors.forename: Valentina
authors.initials: V
authors.lastname: Onnis
authors.forename: Alwyn
authors.initials: A
authors.lastname: Fernandes
authors.forename: David R
authors.initials: DR
authors.lastname: Bell
authors.forename: Martin
authors.initials: M
authors.lastname: Rose
authors.forename: J Craig
authors.initials: JC
authors.lastname: Rowlands
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007529:Isoflavones / Q000737:chemistry* / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000037:antagonists & inhibitors*; D013045:Species Specificity
chemical_list: D007529:Isoflavones; D018336:Receptors, Aryl Hydrocarbon