Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists: Structure-Activity Effects

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology
• Nutraceuticals and Phytochemicals

Background:

• Hydroxylated chalcones are natural compounds and precursors to flavonoids, with a core structure valuable for drug development.
• The aryl hydrocarbon receptor (AhR) is a key regulator of cellular responses, including xenobiotic metabolism and inflammation, particularly in the colon.

Purpose of the Study:

• To investigate the structure-dependent activation of AhR-responsive genes (CYP1A1, CYP1B1, UGT1A1) by various di- and trihydroxychalcones.
• To evaluate the potential of hydroxylated chalcones as AhR agonists in colon cancer cells (Caco2) and normal colonocytes (YAMC).

Main Methods:

• Assessed gene induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells treated with different hydroxylated chalcones.
• Utilized AhR-deficient Caco2 cells to confirm AhR-mediated activity.
• Performed in vitro assays to measure CYP1A1 protein induction and AhR-DNA complex formation, alongside molecular modeling studies.

Main Results:

• Maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells was observed for chalcones with 2,2′-dihydroxy substituents (e.g., 2,2′-dihydroxy-, 2,2′,4′-trihydroxy-, and 2,2′,5′-trihydroxychalcones).
• Other di- and trihydroxychalcones showed minimal to no AhR activity in Caco2 cells.
• Hydroxylated chalcones exhibited minimal activity in YAMC cells, unlike the potent inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

Conclusions:

• Hydroxylated chalcones act as structure-dependent AhR agonists, with specific substitution patterns dictating their activity.
• The findings identify specific hydroxylated chalcones as potent AhR modulators with potential implications for AhR-mediated colonic pathways.
• These phytochemicals may offer therapeutic or preventative strategies for colonic conditions influenced by AhR signaling.