A possible mechanism for decrease in serum thyroxine level by polychlorinated biphenyls in Wistar and Gunn rats
A possible mechanism for decrease in serum thyroxine level by polychlorinated biphenyls in Wistar and Gunn rats
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DOI：
10.1093/toxsci/kfh225
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发表时间：
2004-10-01
影响因子：
3.8
通讯作者：
Degawa, M
中科院分区：
文献类型：
--
作者：
Kato, Y;Ikushiro, S;Degawa, M
我们以前已经证明，在小鼠中，多氯联苯(PCBS)降低血清甲状腺激素(T-4)水平的过程中，T-4葡萄糖醛酸化的UDP-葡萄糖醛酸基转移酶(T-4-UDP-GT)没有增加，尽管在大鼠中，多氯联苯引起的下降通常被认为是通过诱导T-4-UDP-GT、UGT1A1和UGT1A6发生的。在本研究中，为了进一步阐明多氯联苯引起大鼠血清T-4水平下降和UGT1A活性升高之间的关系，我们用Wistar大鼠和Gunn大鼠进行了研究，Gunn大鼠是缺乏UGT1A亚型的Wistar大鼠的一个突变株。多氯联苯、KC500(KC500,100 mg/kg)或2，2‘，4，5，5’-五氯联苯(五氯联苯，112 mg/kg)处理4天后，Wistar大鼠和Gunn大鼠血清总T-4水平均显著下降，但下降幅度无显著差异。同时，KC500和五氯联苯均能显著提高Wistar大鼠T-4-UDP-GT的水平和活性，而对Gunn大鼠无明显影响。此外，在Wistar或Gunn大鼠中，KC500治疗对血清总三碘甲状腺原氨酸(T-3)和促甲状腺激素水平没有显著影响。此外，在Wistar和Gunn大鼠中，经KC500或五氯苯处理后，肝脏中介导T-4和T-3脱碘的I型脱碘酶活性均显著降低。从KC500或五氯苯处理的Wistar和Gunn大鼠的血清中，检测到单羟基和双羟化的多氯联苯代谢产物，它们能与T-4结合的血清蛋白(转甲状腺素)结合。上述结果表明，KC500和五氯苯对Gunn大鼠血清总T-4水平的降低并不依赖于肝脏T-4-UDP-GT活性的升高。这些发现进一步表明，多氯联苯介导的血清T-4水平的降低可能至少部分是通过形成羟化的多氯联苯代谢产物来实现的。此外，即使在Wistar大鼠中，多氯联苯介导的血清T-4水平的下降不仅可能通过肝脏T-4-UDP-GT的增加发生，还可能通过形成羟化的多氯联苯代谢产物而发生。
We have previously demonstrated that in mice, the decrease in serum thyroxine (T-4) level by polychlorinated biphenyls (PCBs) occurs without an increase in the UDP-glucuronosyltransferase (T-4-UDP-GT) for T-4 glucuronidation, although the PCB-induced decrease in rats is generally thought to occur through induction of T-4-UDP-GT, UGT1A1, and UGT1A6. In the present study, to further clarify the relationship between the decrease in serum T-4 level and the increase in UGT1A activity by PCB in rats, we examined the relationship using Wistar rats and Gunn rats, a mutant strain of Wistar rats deficient in UGT1A isoforms. The serum total T-4 level was markedly decreased not only in the Wistar rats but also in the Gunn rats 4 days after treatment with a PCB, Kanechlor-500 (KC500, 100 mg/kg) or 2,2',4,5,5'-pentachlorobiphenyl (PentaCB, 112 mg/kg), and there was no significant difference in magnitude of the decrease between the two rat strains. At the same time, the level and activity of T-4-UDP-GT were significantly increased by treatment with either KC500 or PentaCB in Wistar rats but not in Gunn rats. In addition, no significant change in the level of serum total triiodothyronine (T-3) and thyroid-stimulating hormone by the KC500 treatment was observed in either Wistar or Gunn rats. Furthermore, significant decrease in the activity of hepatic type-I deiodinase, which mediates the deiodization of T-4 and T-3, by treatment with KC500 or PentaCB was observed in both Wistar and Gunn rats. From the serum of KC500- or PentaCB-treated Wistar and Gunn rats, mono- and di-hydroxylated PCB metabolites, which would bind to T-4 binding serum protein (transthyretin), were detected. In conclusion, the present results suggest that the decrease in serum total T-4 level by either KC500 or PentaCB in Gunn rats was not dependent on the increase in hepatic T-4-UDP-GT activity. The findings further suggest that the PCB-mediated decrease in serum T-4 level might occur, at least in part, through formation of the hydroxylated PCB metabolites. Furthermore, even in Wistar rats, the PCB-mediated decrease in serum T-4 level might occur not only through the increase in hepatic T-4-UDP-GT but also via formation of hydroxylated PCB metabolites.