INVESTIGATION ON MECHANISMS OF THYROXINE SUPPRESSIVE EFFECTS OF DIOXINS USING KNOCKOUT MICE

二恶英或多氯联苯对甲状腺素（T4）的抑制作用已有很好的记录。提出了几种可能的机制，如T4-葡萄糖醛酸苷的胆汁排泄增强和与甲状腺素运载蛋白（TTR）（一种主要的T4结合蛋白）的竞争性结合。为了探讨二恶英或多氯联苯抑制T4效应的机制，采用芳烃受体（AhR）缺失小鼠（AhR-/-）和TTR缺失小鼠（TTR-/-）。2，3，7，8-四氯二苯并-p-二恶英（TCDD）和PCB 126显着降低血清总T4（TT 4）水平，同时诱导AhR+/-、TTR+/+和TTR-/-小鼠，但AhR 1/1小鼠中没有。PCB 77和PCB 153显著降低了野生型和TTR-/-小鼠的血清TT 4水平，但TTR-/-小鼠的降低程度远低于TCDD。由于PCB 77容易代谢形成对TTR具有高亲和力的羟基化代谢物，因此认为PCB 77通过与TTR竞争性结合来减少TT 4。TCDD和PCB 126提示通过AhR介导的T4-葡萄糖醛酸苷的增加胆汁排泄来减少TT 4。认为PCB 153通过AhR和TTR以外的因素降低血清TT 4水平，因为PCB 153不诱导肝脏CYP 1A 1，并且几乎不羟基化以结合TTR。

Thyroxine (T4) suppressive effects of dioxins or PCBs were well documented. Several possible mechanisms such as enhanced biliary excretion of T4-glucuronide and competitive binding to transthyretin (TTR), a major T4 binding protein, are proposed. To investigate the mechanisms of T4 suppressive effects of dioxins or PCBs, arylhydrocarbon receptor (AhR)-null mice (AhR-/-) and TTR-null mice (TTR-/-) were employed.2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and PCB126 significantly reduced the serum total T4 (TT4) level concomitant induction of hepatic UGT-1 mRNA and CYP1A1 mRNA in AhR+/-, TTR+/+ and TTR-/-mice but not in AhR1/1 mice. PCB77 and PCB153 significantly reduced the serum TT4 level both in wild type and TTR-/-mice but the reduction in TTR-/-mice was much less compared to TCDD. As PCB77 is easily metabolized to form a hydroxylated metabolite which has high affinity to TTR, PCB77 is thought to reduce TT4 via competitive binding to TTR. TCDD and PCB126 suggested to reduce TT4 by an enhanced biliary excretion of T4-glucuronide mediated by the AhR. PCB153 is thought to reduce serum TT4 level via factors other than AhR and TTR since PCB 153 do not induce hepatic CYP1A1 and is hardly hydroxylated to bind to TTR.