Transcriptional regulation by triiodothyronine of the UDP-glucuronosyltransferase family 1 gene complex in rat liver. Comparison with induction by 3-methylcholanthrene.
This study demonstrates that the expression of the phenol UDP-glucuronosyltransferase 1 gene (UGT1A1) is regulated at the transcriptional level by thyroid hormone in rat liver. Following 3,5, 3'-triiodo-L-thyronine (T3) stimulation in vivo, there is a gradual increase in the amount of UGT1A1 mRNA with maximum levels reached 24 h after treatment. In comparison, induction with the specific inducer, 3-methylcholanthrene (3-MC), results in maximal levels of UGT1A1 mRNA after 8 h of treatment. In primary hepatocyte cultures, the stimulatory effect of both T3 and 3-MC is also observed. This induction is suppressed by the RNA synthesis inhibitor actinomycin D, indicating that neither inducer acts at the level of mRNA stabilization. Indeed, nuclear run-on assays show a 3-fold increase in UGT1A1 transcription after T3 treatment and a 6-fold increase after 3-MC stimulation. This transcriptional induction by T3 is prevented by cycloheximide in primary hepatocyte cultures, while 3-MC stimulation is only partially affected after prolonged treatment with the protein synthesis inhibitor. Together, these data provide evidence for a transcriptional control of UGT1A1 synthesis and indicate that T3 and 3-MC use different activation mechanisms. Stimulation of the UGT1A1 gene by T3 requires de novo protein synthesis, while 3-MC-dependent activation is the result of a direct action of the compound, most likely via the aromatic hydrocarbon receptor complex.
Masmoudi
T
T
Laboratoire de Biochimie Pharmacologique, Faculté de Pharmacie, Université de Bourgogne, 7. Bv. Jeanne d' Arc, Dijon 21033, France.
Hihi
A K
AK
Vázquez
M
M
Artur
Y
Y
Desvergne
B
B
Wahli
W
W
Goudonnet
H
H
D000818:Animals; D002273:Carcinogens / Q000494:pharmacology*; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology; D004790:Enzyme Induction; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics*; D008099:Liver / Q000201:enzymology*; D008748:Methylcholanthrene / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D014158:Transcription, Genetic / Q000187:drug effects; D014284:Triiodothyronine / Q000494:pharmacology*
D002273:Carcinogens; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D014284:Triiodothyronine; D003609:Dactinomycin; D008748:Methylcholanthrene; D003513:Cycloheximide; D014453:Glucuronosyltransferase