The synthetic retinoid AGN 193109 but not retinoic acid elevates CYP1A1 levels in mouse embryos and Hepa-1c1c7 cells

The synthetic retinoid AGN 193109 is a potent pan retinoic acid receptor (R AR) antagonist. Treatment of pregnant mice with a single oral I mg/kg dose of this antagonist on day 8 postcoitum results in severe craniofacial (medi an cleft face or frontonasal deficiency) and eye malformations in virtually all exposed fetuses. Using differential display analysis, we have determin ed that CYP1A1 mRNA levels are elevated in mouse embryos 6 h following trea tment with AGN 193109. Similarly, an elevation in CYP1A1 mRNA levels, prote in levels, and aryl hydrocarbon hydoxylase activity occurs in Hepa-1c1c7 ce lls, with the maximal elevation observed when the cells were treated with 1 0(-5) M AGN 193109 for 4 to 8 h. Elevation in CYP1A1 mRNA levels in mouse e mbryos and Hepa-1c1c7 cells does not occur upon treatment with the natural retinoid, all-trans-retinoic acid. Finally, elevation in CYP1A1 mRNA levels was not observed when mutant Hepa-1c1c7 cells, which are defective in eith er the aryl hydrocarbon receptor (AhR) or aryl hydrocarbon receptor nuclear translocator (ARNT), were treated with AGN 193109. This suggests that the AhR/ARNT pathway and not the RAR/RXR pathway is mediating the elevation of CYP1A1 mRNA levels by AGN 193109, at least in the Hepa-1c1c7 cells. This is the first example of a retinoid that displays the abililty to regulate bot h the RAR/RXR and AhR/ARNT transcriptional regulatory pathways. (C) 2001 Ac ademic Press.