Transcriptional Regulation by Triiodothyronine of the UDP-glucuronosyltransferase Family 1 Gene Complex in Rat Liver

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 (T 3 ) 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 T 3 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 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, 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 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 compound, most likely via the aromatic hydrocarbon receptor complex.

Xanthohumol, a prenylated chalcone from hops, modulates hepatic expression of genes involved in thyroid hormone distribution and metabolism

“…T3 is, on the other side, a potent regulator of Ugt1a1 activity and transcription. With the exception of one in vivo study showing an increase in Ugt1a1 expression after T3 administration 53, other authors reported decreased activity and expression 54, 55, especially with vitamin A as co‐regulator 56. Although we observed an increase in serum T3 after administration with 100 mg XN/kg BW/day XN, we have no evidence that T3 causes this decrease in Ugt1a1 expression.…”

Influence of vitamin A status on the regulation of uridine (5′-)diphosphate-glucuronosyltransferase (UGT) 1A1 and UGT1A6 expression by L-triiodothyronine

“…In a recent study (Masmoudi et al 1996), we found that treatment of rats with L-T3 differentially affected the expression of UGT1A1 and UGT1A6, which catalyse glucuronidation of bilirubin and phenols respectively. L-T3 significantly increased the mRNA encoding UGT1A6, but decreased that of UGT1A1 in rat liver, whereas the opposite situation was observed in thyroidectomised rats (Masmoudi et al 1997a). Thyroid hormones regulate the gene expression of UGT1A1 and UGT1A6 at the transcriptional level without affecting the half-lives of their mRNA.…”

Increase in Rat Liver UDP-Glucuronosyltransferase mRNA by Microsomal Enzyme Inducers that Enhance Thyroid Hormone Glucuronidation

“…The mechanism of induction of UGT1A6 by 3-MC has been well described. A xenobiotic response element (XRE) on UGT1A6, responsible for transcriptional activation by polycyclic aromatic hydrocarbons, mediates de novo transcription of this gene (Emi et al, 1996;Masmoudi et al, 1997). Other mechanisms regulating chemical-mediated increases in UGT mRNA have been indirectly described (Marie and Cresteil, 1989;Roy et al, 1991) or are yet to be resolved (Vargas et al, 1998;Metz et al, 2000).…”