RT Journal Article
SR Electronic
T1 Species-Specific Transcriptional Activity of Synthetic Flavonoids in Guinea Pig and Mouse Cells as a Result of Differential Activation of the Aryl Hydrocarbon Receptor to Interact with Dioxin-Responsive Elements
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 915
OP 924
DO 10.1124/mol.63.4.915
VO 63
IS 4
A1 Jun-guo Zhou
A1 Ellen C. Henry
A1 Christine M. Palermo
A1 Stephen D. Dertinger
A1 Thomas A. Gasiewicz
YR 2003
UL http://molpharm.aspetjournals.org/content/63/4/915.abstract
AB To investigate possible species-specificity of aryl hydrocarbon receptor (AhR)-mediated signal transduction pathways, activities of 2,3,7,8-tetrochlorodibenzo-p-dioxin (TCDD) and six synthetic flavonoids were evaluated in mouse hepatoma and guinea pig adenocarcinoma cells transfected with an AhR-responsive luciferase reporter. Rank order potency in these two cell lines was similar for the ability of these flavonoids to antagonize TCDD-induced reporter gene expression. However, in the presence of flavone alone, a species-specific difference in agonist activity was observed. In guinea pig cells, several flavonoids demonstrated agonist activity up to 50% of the maximum TCDD response. In mouse cells, however, no significant agonist activity was observed at the same concentrations based on luciferase enzyme activity, protein expression, and mRNA analysis. Moreover, competitive ligand-binding assays, using [3H]TCDD in cytosolic fractions, demonstrated that 3′-methoxy-4′-nitroflavone had a similar IC50 in both recombinant cell lines, suggesting that the flavone has similar binding affinity to receptors from both species. However, electrophoretic mobility shift assay using the cytosolic fractions demonstrated that this flavone elicited binding to the DRE by guinea pig but not mouse AhR complex. The dependence of the AhR in this differential interaction was further demonstrated using in vitro synthesized guinea pig and mouse Ah receptors and mouse Arnt. Together, these data suggest that the differential agonist/antagonist activity of these flavone derivatives is caused by the efficacy of these flavonoids in eliciting an AhR conformation that recognizes regulatory response elements in a species-specific manner. The American Society for Pharmacology and Experimental Therapeutics