Fused mesoionic heterocyclic compounds are a new class of aryl hydrocarbon receptor (AhR) agonist of exceptional potency

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 similar to 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 EC50 = 5.05 pM (95% CI = 2.81-9.09 pM) whereas TCDD had an EC50 = 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 EC50 = 65.4 pM (95% Cl = 45.6-93.7 pM) and TCDD an EC50 = 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. (C) 2012 Elsevier Ireland Ltd. All rights reserved.