Vol. 61, Issue 2, 334-342, February 2002

Unique Property of Some Synthetic Retinoids: Activation of the Aryl Hydrocarbon Receptor Pathway

Carlo J. Gambone, Juliet M. Hutcheson, Jerome L. Gabriel, Richard L. Beard, Roshantha A.S. Chandraratna, Kenneth J. Soprano, and Dianne Robert Soprano

Department of Biochemistry (C.J.B., J.M.H., J.L.G., D.R.S.), Fels Institute for Cancer Research and Molecular Biology (K.J.S., D.R.S.), Department of Microbiology and Immunology (K.J.S.), Temple University School of Medicine, Philadelphia, Pennsylvania; and Retinoid Research, Departments of Chemistry and Biology, Allergan, Inc., Irvine, California (R.L.B., R.A.S.C.)

Potential pharmacological applications in the areas of oncology, dermatology, diabetes, and atherosclerosis of synthetic analogs of retinoic acid that target a specific nuclear receptor and/or biological response have generated great interest in the development of new retinoid and rexinoid drugs. The pan-retinoic acid receptor antagonist AGN 193109 has been previously reported to elevate CYP1A1 levels, implicating the aryl hydrocarbon receptor (AhR) as an additional target for this retinoid. AhR is a cytosolic ligand-dependent transcription factor that, in conjunction with the AhR nuclear translocator (Arnt), binds to dioxin response elements (DREs) located in the promoter region of target genes, such as CYP1A1, and induces their transcription. The purpose of these studies was to determine whether additional synthetic retinoids were capable of elevating CYP1A1 levels and to examine the mechanism of this increase in CYP1A. Two additional retinoids, AGN 190730 and AGN 192837, were found to be potent inducers of DRE-driven transcriptional activity; AGN 190730 was the most potent. Moreover, electrophoretic mobility-shift assays demonstrate that AGN 190730 can transform AhR into its active DNA recognition form. In addition, trypsin digestion of AGN 190730-treated AhR reveals a conformational change in the protein similar to the conformational change of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-bound AhR. Finally, competitive binding studies demonstrate that AGN 190730 can inhibit the binding of TCDD to AhR. The sum of the data demonstrates that some synthetic retinoids in addition to activating the retinoic acid receptor/retinoid X receptor pathway are capable of binding to AhR and activating the AhR/Arnt pathway.