SUBSTITUTED FLAVONES AS ARYL-HYDROCARBON (AH) RECEPTOR AGONISTS AND ANTAGONISTS

The structure-dependent aryl hydrocarbon (Ah) receptor agonist and ant agonist activities of the following substituted flavones were investig ated: flavone, 4'-methoxy-, 4'-amino-, 4'-chloro-, 4'-bromo-, 4'-nitro -, 4'-chloro-3'-nitro-, 3'-amino-4'-hydroxy-, 3',4'-dichloro-, and 4'- iodoflavone. The halogenated flavones exhibited competitive Ah recepto r binding affinities (IC50 = 0.79 to 2.28 nM) that were comparable to that observed for 2,?,7,8-tetrachlorodibenzo-p-dioxin (TCDD) (1.78 nM) . The compounds also induced transfor mation of the rat cytosolic Ah r eceptor and induced CYP1A1 gene expression in MCF-7 human breast cance r cells. However, despite the high Ah receptor binding affinities for these responses, the halogenated flavones were > 1000 times less activ e than TCDD for the other responses. Moreover, for other substituted f lavones, there was no correlation between Ah receptor binding affiniti es and their activities as Ah receptor agonists. For example, 4'-amino flavone induced CYP1A1 mRNA levels in MCF-7 cells but exhibited relati vely low Ah receptor binding affinity (IC50 = 362 nM) and did not indu ce transformation of the rat cytosolic Ah receptor. All of the substit uted flavones inhibited TCDD-induced transformation of the Ah receptor , and 4'-iodoflavone, an Ah receptor agonist at high concentrations (1 -50 mu M), inhibited the transformation at concentrations as low as 0. 05 and 0.5 mu M. Subsequent interaction studies with TCDD and 4'-iodof lavone confirmed that the latter compound inhibits induction of CYP1A1 gene expression by TCDD in MCF-7 cells. The results obtained for the substituted flavones suggest that within this structural class of comp ounds, various substituent groups can affect markedly the activity of each individual congener as an Ah receptor agonist or antagonist. Thes e substituent-dependent differences in activity may be related to liga nd-induced conformational changes in the Ah receptor complex and/or su pport the proposed existence of more than one form of the Ah receptor.