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

Hyejin Park, Un Ho Jin, Keshav Karki, Clinton Allred, Laurie A. Davidson, Robert S. Chapkin, Asuka A. Orr, Farrhin Nowshad, Arul Jayaraman, Phanourios Tamamis, Stephen Safe

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2′-dihydroxy substituents and this included 2,2′-dihydroxy-, 2,2′,4′-trihydroxy-, and 2,2′,5′-trihydroxychalcones. In contrast, 2′,4,5′-, 2′3′,4′-, 2′,4,4′-trihydroxy, and 2′,3-, 2′,4-, 2′,4′-, and 2′,5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2′-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.

Original languageEnglish (US)
Pages (from-to)148-159
Number of pages12
JournalToxicological Sciences
Issue number1
StatePublished - Mar 1 2021


  • Ah receptor
  • CYP1A1
  • CYP1B1
  • UGT1A1
  • cell
  • chalcones
  • colon
  • computational modeling
  • gene-expression
  • structure-activity

ASJC Scopus subject areas

  • Toxicology


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