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 (RAR) antagonist. Treatment of pregnant mice with a single oral 1 mg/kg dose of this antagonist on day 8 postcoitum results in severe craniofacial (median cleft face or frontonasal deficiency) and eye malformations in virtually all exposed fetuses. Using differential display analysis, we have determined that CYP1A1 mRNA levels are elevated in mouse embryos 6 h following treatment with AGN 193109. Similarly, an elevation in CYP1A1 mRNA levels, protein levels, and aryl hydrocarbon hydoxylase activity occurs in Hepa-1c1c7 cells, with the maximal elevation observed when the cells were treated with 10(-5) M AGN 193109 for 4 to 8 h. Elevation in CYP1A1 mRNA levels in mouse embryos 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 either 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 both the RAR/RXR and AhR/ARNT transcriptional regulatory pathways.
Soprano
D R
DR
Department of Biochemistry, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
Gambone
C J
CJ
Sheikh
S N
SN
Gabriel
J L
JL
Chandraratna
R A
RA
Soprano
K J
KJ
Kochhar
D M
DM
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D004622:Embryo, Mammalian / Q000187:drug effects* / Q000201:enzymology; D005260:Female; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors*; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
C497397:Arnt protein, mouse; D004268:DNA-Binding Proteins; D009281:Naphthalenes; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D018168:Receptors, Retinoic Acid; D014157:Transcription Factors; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D014212:Tretinoin; D019363:Cytochrome P-450 CYP1A1; C096920:AGN 193109