{"doi":"10.1093/toxsci/kfaa179","title":"Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists: Structure-Activity Effects","abstract":"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.","journal":"Toxicological Sciences","year":2020,"id":112046,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9563,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":265696,"name":"Un-Ho Jin","orcid":null,"position":1,"is_corresponding":false},{"id":261524,"name":"Keshav Karki","orcid":null,"position":2,"is_corresponding":false},{"id":461257,"name":"Clinton D. Allred","orcid":"0000-0002-4884-841X","position":3,"is_corresponding":false},{"id":435790,"name":"Laurie A. Davidson","orcid":"0000-0002-4159-4680","position":4,"is_corresponding":false},{"id":241898,"name":"Robert S. Chapkin","orcid":"0000-0002-6515-3898","position":5,"is_corresponding":false},{"id":270827,"name":"Asuka A. Orr","orcid":"0000-0003-4628-526X","position":6,"is_corresponding":false},{"id":530700,"name":"Farrhin Nowshad","orcid":"0000-0002-0959-7005","position":7,"is_corresponding":false},{"id":265697,"name":"Arul Jayaraman","orcid":null,"position":8,"is_corresponding":false},{"id":270829,"name":"Phanourios Tamamis","orcid":"0000-0002-3342-2651","position":9,"is_corresponding":false},{"id":260421,"name":"Stephen Safe","orcid":"0000-0002-2115-3060","position":10,"is_corresponding":false},{"id":530699,"name":"Hyejin Park","orcid":"0000-0001-9165-6045","position":0,"is_corresponding":true}],"reference_count":44,"raw_metadata":null,"created_at":"2026-07-18T23:13:09.353152Z","pmid":"33263770","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}