Isoflavones as Ah Receptor Agonists in Colon-Derived Cell Lines: Structure-Activity Relationships

Hyejin Park, Un Ho Jin, Asuka A. Orr, Stephanie P. Echegaray, Laurie A. Davidson, Clinton D. Allred, Robert S. Chapkin, Arul Jayaraman, Kyongbum Lee, Phanourios Tamamis, Stephen Safe

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

Many of the protective responses observed for flavonoids in the gastrointestinal track resemble aryl hydrocarbon receptor (AhR)-mediated effects. Therefore, we examined the structure-activity relationships of isoflavones and isomeric flavone and flavanones as AhR ligands on the basis of their induction of CYP1A1, CYP1B1, and UGT1A1 gene expression in colon cancer Caco2 cells and young adult mouse colonocyte (YAMC) cells. Caco2 cells were significantly more Ah-responsive than YAMC cells, and this was due, in part, to flavonoid-induced cytotoxicity in the latter cell lines. The structure-activity relationships for the flavonoids were complex and both response and cell context specific; however, there was significant variability in the AhR activities of the isomeric substituted isoflavones and flavones. For example, 4′,5,7-trihydroxyisoflavone (genistein) was AhR-inactive whereas 4′,5,7-trihydroxyflavone (apigenin) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells. In contrast, both 5,7-dihydroxy-4-methoxy substituted isoflavone (biochanin A) and flavone (acacetin) induced all three AhR-responsive genes; 4′,5,7-trimethoxyisoflavone was a potent AhR agonist, and the isomeric flavone was AhR-inactive. These results coupled with simulation studies modeling flavonoid interaction within the AhR binding pocket demonstrate that the orientation of the substituted phenyl ring at C-2 (flavones) or C-3 (isoflavones) on the common 4-H-chromen-4-one ring strongly influences the activities of isoflavones and flavones as AhR agonists.

Original languageEnglish (US)
Pages (from-to)2353-2364
Number of pages12
JournalChemical Research in Toxicology
Volume32
Issue number11
DOIs
StatePublished - Nov 18 2019

ASJC Scopus subject areas

  • Toxicology

Fingerprint Dive into the research topics of 'Isoflavones as Ah Receptor Agonists in Colon-Derived Cell Lines: Structure-Activity Relationships'. Together they form a unique fingerprint.

Cite this