RETINOIDS AND THE ARYLHYDROCARBON RECEPTOR PATHWAY

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The actions of retinoic acid (RA) are mediated by a group of ligand-dependent transcription factors (nuclear receptors) called retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Since the discovery of the RARs and RXRs, thousands of synthetic retinoids, many of which are non-isoprenoid in structure, have been developed to target a specific RAR/RXR subtype or function. Preliminary data demonstrate that one non-isoprenoid retinoid, AGN193109, can elevate the level of CYP1A1 mRNA in mouse embryos and Hepa-1c1c7 cells. Data are presented which suggest that this regulation of CYP1A1 mRNA is mediated by the aryl hydrocarbon receptor (AhR)/Ah nuclear translocator (Arnt) pathway. The AhR/Arnt pathway has been demonstrated to be regulated by polyaromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs) such as benzo[a]pyrene and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), respectively. We hypothesize that AGN193109 and potentially other non-isoprenoid and retinoids can mimic PAHs and HAHs and activate AhR causing an induction in CYP1A1 mRNA levels and potentially other [Ah] battery genes along with binding and activating/antagonizing RARs and RXRs. This is the first example of two quite distinct transcriptional regulatory pathways (AhR/Arnt and RAR/RXR) which could potentially be regulated simultaneously by the same retinoid. Since the activation of AhR by PAHs and HAHs can result in severe adaptive, carcinogenic and potentially toxic responses in humans, it is important: (1) to determine the role of the AhR/Arnt pathway in the regulation of CYP1A1 mRNA levels by AGN193109; (2) to examine the structural features of synthetic retinoids which are responsible for the eleveation of CYP1A1 mRNA levels and; (3) to assess the physiological consequences of the elevation of CYP1A1 mRNA levels by AGN193109 and potentially other non-isoprenoid retinoids. The findings from these studies will have important implications in the design and use of synthetic retinoids for pharmacological application since it would be undesirable to activate the AhR/Arnt pathway along the desired modulation of the RAR/RXR pathway.