Increased biliary excretion of thyroxine by microsomal enzyme inducers.
Increased biliary excretion of thyroxine by microsomal enzyme inducers.
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DOI：
10.1006/taap.2001.9278
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发表时间：
2001-11
影响因子：
3.8
通讯作者：
N. Vansell;C. Klaassen
中科院分区：
文献类型：
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作者：
N. Vansell;C. Klaassen
内分泌干扰物促进甲状腺肿瘤的甲状腺外机制被认为是葡萄糖醛酸化增加和甲状腺素（T（4））的胆汁消除，随后是下丘脑-垂体-甲状腺轴的破坏。一种化学物质在体外增加T（4）葡萄糖醛酸化的能力与降低血清T（4）浓度的能力相关。孕烯醇酮-16 α-腈（PCN）、3-甲基氯蒽（3-MC）和多氯联苯1254（PCB）均能增加大鼠肝微粒体中的T（4）葡萄糖醛酸化，并降低血清T（4）。然而，血清T（4）的降低是否直接由体内T（4）葡萄糖醛酸化和胆汁排泄的增加引起，尚未得到彻底的研究。微粒体酶诱导剂处理后血清T（4）浓度降低是否会引起血清促甲状腺激素（TSH）升高，这是甲状腺细胞增殖的主要刺激因素，目前还不清楚，因为只有PCN处理会增加血清TSH。本研究旨在确定体内T（4）-葡萄糖醛酸苷胆汁排泄增加是否是血清T（4）降低和血清TSH升高的原因。雄性大鼠喂食对照饲料或含有1000 ppm PCN、250 ppm 3-MC或100 ppm PCB的饲料7天。然后给动物静脉注射[（125）I]T（4），收集胆汁2 h。通过反相HPLC-γ-检测分析胆汁中的放射性标记代谢物。PCN、3-MC和PCB处理分别使血清T（4）浓度降低42%、45%和73%，而PCN仅使TSH升高（180%）。经PCN、3-MC和PCB处理后，[（125）I]甲状腺原氨酸的胆汁排泄量分别增加103%、157%和193%。T（4）-葡糖苷酸是胆汁中的主要代谢产物，占对照组放射性标记代谢产物的86%。3-MC和PCB使胆汁中的T（4）-葡萄糖醛酸苷排泄量分别增加161%和226%，但PCN仅增加55%。所有治疗对[（125）I]T的尿排泄均无任何影响（4）。因此，增加的葡萄糖醛酸化和胆汁排泄的T（4）似乎可能是负责减少血清T（4）产生的微粒体酶诱导剂。此外，微粒体酶诱导剂治疗引起的T（4）胆汁排泄增加与TSH的变化不一致。因此，可以得出结论，血清TSH的差异变化并不源于胆汁中T（4）排泄的差异增加。
The extrathyroidal mechanism by which endocrine disruptors promote thyroid tumors has been proposed to be increased glucuronidation and biliary elimination of thyroxine (T(4)), followed by disruption of the hypothalamic-pituitary-thyroid axis. The ability of a chemical to increase T(4) glucuronidation in vitro correlates with the ability to reduce serum T(4) concentrations. Pregnenolone-16alpha-carbonitrile (PCN), 3-methylchloranthrene (3-MC), and Aroclor 1254 (PCB) each increase T(4) glucuronidation in rat liver microsomes and reduce serum T(4). However, whether reductions in serum T(4) result directly from increases in T(4) glucuronidation and biliary excretion in vivo has not been thoroughly examined. It is also unclear whether reduced serum T(4) concentrations following microsomal enzyme inducer treatment elicit increases in serum thyrotropin (TSH), the primary stimulus for thyroid cell proliferation, because only PCN treatment increases serum TSH. This study sought to determine whether increases in T(4)-glucuronide biliary excretion in vivo are responsible for reductions in serum T(4) and increases in serum TSH. Male rats were fed control diet or diet containing either 1000 ppm PCN, 250 ppm 3-MC, or 100 ppm PCB for 7 days. Animals were then given [(125)I]T(4) iv, and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with gamma-detection. PCN, 3-MC, and PCB treatments reduced serum T(4) concentrations by 42, 45, and 73%, respectively, while TSH was only increased by PCN (180%). The biliary excretion of [(125)I]thyronines was increased 103% by PCN, 157% by 3-MC, and 193% by PCB. T(4)-glucuronide was the primary metabolite in bile, accounting for up to 86% of the radiolabeled metabolites in controls. The amount of T(4)-glucuronide excreted in bile was increased 161% and 226% by 3-MC and PCB, respectively, but was only increased 55% by PCN. None of the treatments had any effect on the urinary excretion of [(125)I]T(4). Thus, increased glucuronidation and biliary excretion of T(4) appears likely to be responsible for reductions in serum T(4) produced by microsomal enzyme inducers. Furthermore, increases in T(4) biliary excretion produced by microsomal enzyme inducer treatment are not consistent with changes in TSH. Thus, it can be concluded that differential changes in serum TSH do not stem from differential increases in T(4) biliary excretion.