TY - JOUR
T1 - Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists
T2 - Structure-Activity Effects
AU - Park, Hyejin
AU - Jin, Un Ho
AU - Karki, Keshav
AU - Allred, Clinton
AU - Davidson, Laurie A.
AU - Chapkin, Robert S.
AU - Orr, Asuka A.
AU - Nowshad, Farrhin
AU - Jayaraman, Arul
AU - Tamamis, Phanourios
AU - Safe, Stephen
N1 - © The Author(s) 2020. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please e-mail: [email protected].
PY - 2021/3/1
Y1 - 2021/3/1
N2 - 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.
AB - 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.
KW - Ah receptor
KW - CYP1A1
KW - CYP1B1
KW - UGT1A1
KW - cell
KW - chalcones
KW - colon
KW - computational modeling
KW - gene-expression
KW - structure-activity
KW - Caco-2 Cells
KW - Receptors, Aryl Hydrocarbon/genetics
KW - Humans
KW - Polychlorinated Dibenzodioxins
KW - Cytochrome P-450 CYP1A1/genetics
KW - Animals
KW - Chalcones/toxicity
KW - Cytochrome P-450 CYP1B1/genetics
KW - Protein Binding
KW - Mice
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UR - http://www.scopus.com/inward/citedby.url?scp=85102403154&partnerID=8YFLogxK
U2 - 10.1093/toxsci/kfaa179
DO - 10.1093/toxsci/kfaa179
M3 - Article
C2 - 33263770
AN - SCOPUS:85102403154
SN - 1096-6080
VL - 180
SP - 148
EP - 159
JO - Toxicological Sciences
JF - Toxicological Sciences
IS - 1
ER -