title: Fused mesoionic heterocyclic compounds are a new class of aryl hydrocarbon receptor (AhR) agonist of exceptional potency.
abstract: 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is one of the most potent ligands of the aryl hydrocarbon receptor (AhR). Here, we show that a novel fused mesoionic heterocyclic compound (AZ1) is ∼5-fold more potent than TCDD in both rat and human cell lines at inducing cytochrome P4501A1 RNA. In rat H4IIE cells, AZ1 gave an EC(50)=5.05 pM (95% CI=2.81-9.09 pM) whereas TCDD had an EC(50)=25.5 pM (95% CI=18.2-36.0 pM). AZ1 was also more potent than TCDD (5-10-fold) at inducing the AhR-related CYP1A2 and CYP1B1 genes, showing that AZ1 is more potent at inducing multiple genes. In human MCF-7 cells AZ1 gave an EC(50)=65.4 pM (95% CI=45.6-93.7 pM) and TCDD an EC(50)=241 pM (95% CI=161-362 pM), showing that AZ1 was more potent than TCDD at inducing CYP1A1 RNA in multiple species. Finally, the compound bound to rat cytosolic AhR with 6-fold higher affinity than TCDD, showing that the highly potent agonism of this substance is mediated via a high affinity for the receptor. This data shows that this novel compound, which shares structural similarities with various naphthoflavones, is a potent ligand of the AhR.
authors.affiliation: School of Biology, University Park, University of Nottingham, Nottingham NG7 2RD, UK.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Wall
authors.forename: David R
authors.initials: DR
authors.lastname: Bell
authors.forename: Rana
authors.initials: R
authors.lastname: Bazzi
authors.forename: Alwyn
authors.initials: A
authors.lastname: Fernandes
authors.forename: Martin
authors.initials: M
authors.lastname: Rose
authors.forename: J Craig
authors.initials: JC
authors.lastname: Rowlands
authors.forename: Ian R
authors.initials: IR
authors.lastname: Mellor
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics / Q000378:metabolism; D065633:Cytochrome P-450 CYP1B1; D003580:Cytochromes / Q000235:genetics / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000633:toxicity*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C587352:3-hydroxy-2-(4-(trifluoromethyl)phenyl)(1,2,3)triazolo(1,5-a)quinolinium; D003580:Cytochromes; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D000072317:Polychlorinated Dibenzodioxins; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D001189:Aryl Hydrocarbon Hydroxylases; C504573:CYP1A2 protein, human; C585496:CYP1B1 protein, human; C017170:Cyp1a2 protein, rat; C585499:Cyp1b1 protein, rat; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1