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Isoflavones as Ah Receptor Agonists in Colon-Derived Cell Lines: Structure-Activity Relationships
Hyejin Park1, Un-Ho Jin1, Asuka A Orr2
1Department of Veterinary Physiology and Pharmacology , Texas A&M University , College Station , Texas 77843 , United States.
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.
Insights
Flavonoids, like genistein and apigenin, interact with the aryl hydrocarbon receptor (AhR). Their structure dictates activity, with specific orientations influencing gene expression in colon cells.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Flavonoids exhibit protective effects in the gastrointestinal tract, potentially via aryl hydrocarbon receptor (AhR) pathways.
- Understanding flavonoid-AhR interactions is crucial for elucidating their biological activities and therapeutic potential.
Purpose of the Study:
- To investigate the structure-activity relationships of isoflavones, flavones, and flavanones as AhR ligands.
- To determine the impact of flavonoid structure on the induction of AhR-responsive genes (CYP1A1, CYP1B1, UGT1A1) in colon cell models.
Main Methods:
- Utilized Caco2 and young adult mouse colonocyte (YAMC) cell lines to assess AhR ligand activity.
- Measured induction of CYP1A1, CYP1B1, and UGT1A1 gene expression in response to various flavonoids.
- Employed molecular modeling and simulation studies to analyze flavonoid binding within the AhR pocket.
Main Results:
- Caco2 cells showed higher AhR responsiveness compared to YAMC cells, partly due to lower flavonoid-induced cytotoxicity.
- Isoflavone and flavone isomeric structures displayed significant variability in AhR agonist/antagonist activity.
- Genistein (isoflavone) was AhR-inactive, while apigenin (flavone) induced AhR-responsive genes; structural differences in phenyl ring orientation were key.
Conclusions:
- Flavonoid activity as AhR agonists is highly dependent on their chemical structure and the cellular context.
- The orientation of the phenyl ring on the chromen-4-one core significantly influences the interaction of isoflavones and flavones with the AhR.
- These findings provide insights into the molecular mechanisms underlying flavonoid-AhR signaling and its implications for colon health.
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