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-glucuron osyltransferase I gene (UGT1A1) is regulated at the transcriptional le vel by thyroid hormone in rat liver, Following 3,5,3'-triiodo-L-thyron ine (T-3) stimulation in vivo, there is a gradual increase in the amou nt 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 treatme nt, In primary hepatocyte cultures, the stimulatory effect of both T-3 and 3-MC is also observed. This induction is suppressed by the RNA sy nthesis 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 T-3 treatment and a 6 -fold increase after 3-MC stimulation, This transcriptional induction by T-3 is prevented by cycloheximide in primary hepatocyte cultures, w hile 3-MC stimulation is only partially affected after prolonged treat ment with the protein synthesis inhibitor, Together, these data provid e evidence for a transcriptional control of UGT1A1 synthesis and indic ate that T-3 and 3-MC use different activation mechanisms, Stimulation of the UGT1A1 gene by T-3 requires de novo protein synthesis, while 3 -MC-dependent activation is the result of a direct action of the compo und, most likely via the aromatic hydrocarbon receptor complex.