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

详细信息	查看全文 | 推荐本文 |

• 作者：Richard J. Wall^a ; Guochun He^b ; Michael S. Denison^b ; Cenzo Congiu^c ; Valentina Onnis^c ; Alwyn Fernandes^d ; David R. Bell^e ; Martin Rose^d ; J. Craig Rowlands^f ; Gianfranco Balboni^c ; ^{gbalboni@unica.it} ; Ian R. Mellor^a ; ^{ian.mellor@nottingham.ac.uk}
• 关键词：AhR ; aryl hydrocarbon receptor ; TCDD ; 2 ; 3 ; 7 ; 8-tetrachlorodibenzo-p-dioxin ; Chr ; 2-amino-isoflavone ; qRT-PCR ; quantitative real-time polymerase chain reaction
• 刊名：Toxicology
• 出版年：2012
• 期刊代码：47_0300483x
• 类别：pha
• 出版时间：16 July, 2012
• 卷：297
• 期：1-3
• 页码：26-33
• 文件大小：467 K

摘要

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.