A possible mechanism for decrease in serum thyroxine level by polychlorinated biphenyls

在本研究中，我们确定了用Kanechlor-500（KC 500）以相对低的剂量（10 mg/kg，i. p.，每日1次，连续10天）可使血清总甲状腺素（T_4）水平降低，并进一步探讨了KC_（500）降低T_4的确切机制。KC_（500）末次给药后4天，Wistar大鼠和UGT_（1A）缺陷Wistar（古恩）大鼠血清总T_4和游离T_4水平均显著降低，而肝T_4-UDP-葡萄糖醛酸转移酶（T_4-UDP-GT）活性显著升高，而古恩大鼠无此变化。Wistar和古恩大鼠血清促甲状腺激素水平无明显变化。KC <125>500预处理的Wistar大鼠和古恩大鼠血清中[^ I]T_4的清除速度比相应的对照组（KC 500未处理）大鼠快。结果表明，在10 ~ 20天内，[^<125>I]T_4在几种组织中的蓄积水平均升高，尤以肝脏为甚。 ...更多信息 KC 500预处理大鼠。结果表明，KC_（500）连续给药可使Wistar大鼠和古恩大鼠血清总T_4水平显著降低，并进一步表明KC_（500）引起的血清总T_4水平降低是通过增加T_4在多种组织中的蓄积而实现的，尤其是肝脏。而不是增加肝脏T_4-UDP-GT活性。为了阐明负责人肝脏中甲状腺激素T_4葡萄糖醛酸化的UGT亚型，比较了重组人UGT异构体和7个人肝微粒体的T_4-葡萄糖醛酸化活性。结果表明，人肝脏中T_4的葡萄糖醛酸化是由UGT 1A亚家族酶介导的，尤其是UGT 1A 1和UGT 1A 3，并进一步提示人肝脏中UGT 1A 1和UGT 1A 3表达水平的个体差异。对多氯联苯引起的动物（包括人）血清T_4水平降低的易感性还需进一步研究。少

In the present study, we determined whether or not a consecutive treatment with Kanechlor-500 (KC500) at a relatively low dose (10 mg/kg, i.p., once daily for 10 days) results in decrease in the level of serum total thyroxine (T_4) and further investigated an exact mechanism for the KC500-induced decrease in the T_4. At 4 days after final treatment with KC500, the serum total T_4 and free T_4 levels were markedly decreased in both Wistar and UGT1A-deficient Wistar (Gunn) rats, while significant increases in hepatic T_4-UDP-glucuronosyltransferase (T_4-UDP-GT) activity were observed in Wistar rats but not in Gunn rats. Level of serum thyroid-stimulating hormone was not significantly changed in either Wistar or Gunn rats. Clearance from serum of the [^<125>I]T_4 administered to the KC500-pretreated Wistar and Gunn rats was faster than that to the corresponding control (KC500-untreated) rats. The accumulated level of [^<125>I]T_4 was increased in several tissues, especially the liver, in … More the KC500-pretreated rats. The present findings demonstrated that a consecutive treatment with KC500 resulted in significant decrease in level of serum total T_4 in both Wistar and Gunn rats and further indicated that the KC500-induced decrease would occur through increase in accumulation of T_4 in several tissues, especially the liver, rather than increase in hepatic T_4-UDP-GT activity.To clarify the UGT isoform(s) responsible for the glucuronidation of thyroid hormone T_4 in the human liver, the T_4-glucuronidation activities of recombinant human UGT isoforms and 7 individual human liver microsomes were comparatively examined. The findings strongly indicated that glucuronidation of T_4 in the human liver was mediated by UGT1A subfamily enzymes, especially UGT1A1 and UGT1A3, and further suggested that the interindividual difference would come from that in the expression levels of UGT1A1 and UGT1A3 in individual human livers. Further studies are necessary for understanding the susceptibility toward a PCB-mediated decrease in serum T_4 level in animals including humans. Less