Received for publication June 1, 2005.
Revised July 22, 2005.
Accepted for publication July 22, 2005.

DECREASE IN SERUM THYROXINE LEVEL BY PHENOBARBITAL IN RATS IS NOT NECESSARILY DEPENDENT ON INCREASE IN HEPATIC UDP-GLUCURONOSYLTRANSFERASE

Abstract

We have previously reported that there is a poor correlation between increase in the levels of UGT1A1 and UGT1A6 and decrease in the levels of serum total thyroxine (T₄) and free T₄ in phenobarbital (PB)-treated rats, although the PB-induced decrease in rats is generally thought to occur through induction of the UDP-glucuronosyltransferase (T₄-UDP-GT: UGT1A1 and UGT1A6). In the present study, to clarify a relationship between the decrease in serum T₄ level and the increase in the T₄-UDP-GT activity by PB in rats, we examined the relationship using Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. Levels of serum total T₄, free T₄ and total triiodothyronine (T₃) were markedly decreased in not only Wistar rats but also Gunn rats 1 day after the final administration of PB (80 mg/kg, i.p., once daily for 4 days), and no significant difference in magnitude of the decrease between Wistar and Gunn rats was observed. On the other hand, the level and activity of T₄-UDP-GT were significantly increased by treatment with PB in Wistar rats but not in Gunn rats. Furthermore, significant decrease in the activity of hepatic type-I iodothyronine deiodinase, which mediates the deiodination of T₄ and T₃, by PB treatment was observed in both Wistar and Gunn rats. In addition, no significant change in the level of serum thyroid-stimulating hormone, the activity of hepatic sulfotransferase and the binding of [¹²⁵I]T₄ to serum transthyretin and albmin by PB treatment was observed in either Wistar or Gunn rats. In conclusion, the present results demonstrate that the decrease in serum total T₄ level by PB in Gunn rats is not dependent on the increase in hepatic T₄-UDP-GT activity and suggest that even in Wistar rats, the PB-induced decrease in serum T₄ level dose not occur only through increase in hepatic T₄-UDP-GT.

Key words: endocrine regulation, hormonal regulation, liver microsomes, toxicology, UDP glucuronyltransferases

This article has been cited by other articles:

				Y. Kato, S.-i. Ikushiro, R. Takiguchi, K. Haraguchi, N. Koga, S. Uchida, T. Sakaki, S. Yamada, J. Kanno, and M. Degawa A Novel Mechanism for Polychlorinated Biphenyl-Induced Decrease in Serum Thyroxine Level in Rats Drug Metab. Dispos., October 1, 2007; 35(10): 1949 - 1955. [Abstract] [Full Text] [PDF]

				K. K. Miles, F. K. Kessler, L. J. Webb, P. C. Smith, and J. K. Ritter Adenovirus-Mediated Gene Therapy to Restore Expression and Functionality of Multiple UDP-Glucuronosyltransferase 1A Enzymes in Gunn Rat Liver J. Pharmacol. Exp. Ther., September 1, 2006; 318(3): 1240 - 1247. [Abstract] [Full Text] [PDF]