Transcriptional regulation by triiodothyronine of the UDP-glucuronosyltransferase family 1 gene complex in rat liver. Comparison with induction by 3-methylcholanthrene

J Biol Chem. 1997 Jul 4;272(27):17171-5. doi: 10.1074/jbc.272.27.17171.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogens / pharmacology*
  • Cycloheximide / pharmacology
  • Dactinomycin / pharmacology
  • Enzyme Induction
  • Glucuronosyltransferase / biosynthesis
  • Glucuronosyltransferase / genetics*
  • Liver / enzymology*
  • Methylcholanthrene / pharmacology*
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Transcription, Genetic* / drug effects
  • Triiodothyronine / pharmacology*

Substances

  • Carcinogens
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Triiodothyronine
  • Dactinomycin
  • Methylcholanthrene
  • Cycloheximide
  • Glucuronosyltransferase