# Differential Interactions of Flavonoids with the Aryl Hydrocarbon Receptor In Silico and Their Impact on Receptor Activity In Vitro

## TL;DR

This study explores how different flavonoids interact with a cancer-related receptor, revealing new insights into their potential as cancer treatments.

## Contribution

The study identifies naringenin as a novel AHR antagonist and evaluates flavonoid binding affinities and in vitro effects on AHR activity.

## Key findings

- Chrysin, apigenin, naringenin, and quercetin showed high AHR binding affinity in silico.
- All tested flavonoids inhibited AHR activity in vitro in a dose-dependent manner.
- Naringenin exhibited newly described antagonistic potential against AHR.

## Abstract

The molecular mechanisms underlying the observed anticancer effects of flavonoids remain unclear. Increasing evidence shows that the aryl hydrocarbon receptor (AHR) plays a crucial role in neoplastic disease progression, establishing it as a potential drug target. This study evaluated the potential of hydroxy flavonoids, known for their anticancer properties, to interact with AHR, both in silico and in vitro, aiming to understand the mechanisms of action and identify selective AHR modulators. A PAS-B domain homology model was constructed to evaluate in silico interactions of chrysin, naringenin, quercetin apigenin and agathisflavone. The EROD activity assay measured the effects of flavonoids on AHR’s activity in human breast cancer cells (MCF7). Simulations showed that chrysin, apigenin, naringenin, and quercetin have the highest AHR binding affinity scores (−13.14 to −15.31), while agathisflavone showed low scores (−0.57 and −5.14). All tested flavonoids had the potential to inhibit AHR activity in a dose-dependent manner in the presence of an agonist (TCDD) in vitro. This study elucidates the distinct modulatory effects of flavonoids on AHR, emphasizing naringenin’s newly described antagonistic potential. It underscores the importance of understanding flavonoid’s molecular mechanisms, which is crucial for developing novel cancer therapies based on these molecules.