Structure-activity relationships among mono- and dihydroxy flavones as aryl hydrocarbon receptor (AhR) agonists or antagonists in CACO2 cells

芳香烃受体 黄酮类 CYP1B1型 化学 兴奋剂 敌手 受体 药理学 立体化学 生物化学 转录因子 基因 生物 细胞色素P450 色谱法
作者
Hyejin Park,Un-Ho Jin,Gregory G. Martin,Robert S. Chapkin,Laurie A. Davidson,Kyongbum Lee,Arul Jayaraman,Stephen Safe
出处
期刊:Chemico-Biological Interactions [Elsevier]
卷期号:365: 110067-110067 被引量:3
标识
DOI:10.1016/j.cbi.2022.110067
摘要

Unsubstituted flavone induced CYP1A1, CYP1B1 and UGT1A1 gene expression in Caco2 cells and was characterized as an aryl hydrocarbon receptor (AhR) agonist. The structure-activity relationships among 15 mono- and dihydroxyflavones showed that addition of one or two hydroxyl groups resulted in active (e.g.: 5- and 6- mono- and 5,6-dihydroxyflavones) and inactive (e.g.: 7-mono, 7,4′ and 6,4′-dihydroxyflavones) AhR ligands. Ligand docking studies of flavone, mono- and dihydroxyflavones to the human AhR resulted in similar docking scores that varied from −3.48 to −4.58 kcal/mol and these values did not distinguish between AhR-active and AhR-inactive mono- and dihydroxyflavones. The AhR-inactive flavones were subsequently investigated as AhR antagonists by determining their activities as inhibitors of TCDD-induced expression of CYP1A1, CYP1AA2 and UGT 1A1 gene expression in Caco2 cells. Initial studies with 7,4′-dihydroxyflavone showed that this compound was an AhR antagonist in Caco2 cells and resembled the activity of the classical AhR antagonist CH223191. With few exceptions most of the remaining AhR-inactive compounds in terms of inducing AhR responsive genes were also AhR antagonists. Thus, based on modeling studies, mono- and dihydroxyflavones bind with similar affinities to the AhR and exhibit AhR agonist or antagonist activities, however, the structural requirements (substitution patterns) for predicting these opposing activities were not apparent and could only be determined using bioassays.
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