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

School of Pharmaceutical Sciences and the 21^st Century Centers of Excellence Program, University of Shizuoka, Shizuoka, Japan (Y.K., H.S., S.Y., M.D.); and Biotechnology Research Center, Faculty of Engineering, Toyama Prefectural University, Toyama, Japan (S.I.)

We have previously reported that there is a poor correlation between increase in the levels of UDP-glucuronosyltransferases, 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 not only in Wistar rats but also in 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 albumin 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 does not occur only through increase in hepatic T₄-UDP-GT.

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