Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase
Decrease in serum thyroxine level by phenobarbital in rats is not necessarily dependent on increase in hepatic UDP-glucuronosyltransferase
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DOI：
10.1124/dmd.105.005744
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发表时间：
2005-11-01
影响因子：
3.9
通讯作者：
Degawa, M
中科院分区：
文献类型：
--
作者：
Kato, Y;Suzuki, H;Degawa, M
我们以前曾报道，苯巴比妥（PB）处理大鼠的UDP-葡萄糖醛酸转移酶（UGT 1A1和UGT 1A6）水平升高与血清总甲状腺素（T-4）和游离T-4水平降低之间的相关性较差，尽管通常认为PB诱导的大鼠降低是通过诱导UDP-葡萄糖醛酸转移酶发生的（T-4-UDP-GT：UGT1A1和UGT1A6）。在本研究中，为了阐明大鼠中血清T-4水平的降低与PB引起的T-4-UDP-GT活性升高之间的关系，我们使用UGT 1A亚型缺陷的Wistar大鼠的突变品系古恩大鼠（Gunn rats）来研究该关系。在最后一次给予PB（80 mg/kg i.p.，每天一次，持续4天），并且未观察到Wistar和古恩大鼠之间的降低幅度的显著差异。另一方面，PB处理可显著提高Wistar大鼠T-4-UDP-GT的水平和活性，但对古恩大鼠无明显影响。此外，在Wistar和古恩大鼠中均观察到PB处理介导T-4和T-3脱碘的肝I型碘甲腺原氨酸脱碘酶活性显著降低。此外，在Wistar或古恩大鼠中均未观察到PB处理对血清促甲状腺激素水平、肝磺基转移酶活性以及[I-125] T-4与血清甲状腺素运载蛋白和白蛋白结合的显著变化。总之，目前的结果表明，PB降低古恩大鼠血清总T-4水平并不依赖于肝脏T-4-UDP-GT活性的增加，并表明即使在Wistar大鼠中，PB诱导的血清T-4水平降低并不只是通过肝脏T-4-UDP-GT的增加而发生。
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 (T-4) and free T-4 in phenobarbital (PB)-treated rats, although the PB-induced decrease in rats is generally thought to occur through induction of the UDP-glucuronosyltransferase (T-4-UDP- GT: UGT1A1 and UGT1A6). In the present study, to clarify a relationship between the decrease in serum T-4 level and the increase in the T-4- 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 T-4, free T-4, and total triiodothyronine (T-3) 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 T-4-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 T-4 and T-3, 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 [I-125] T-4 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 T-4 level by PB in Gunn rats is not dependent on the increase in hepatic T-4-UDP-GT activity and suggest that even in Wistar rats, the PB-induced decrease in serum T-4 level does not occur only through increase in hepatic T-4-UDP-GT.