Effect of microsomal enzyme inducers on the biliary excretion of triiodothyronine (T(3)) and its metabolites.
Effect of microsomal enzyme inducers on the biliary excretion of triiodothyronine (T(3)) and its metabolites.
复制标题
微粒体酶诱导剂对三碘甲状腺原氨酸（T(3)）及其代谢物胆汁排泄的影响。
DOI：
10.1093/toxsci/65.2.184
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Klaassen,CurtisD
中科院分区：
文献类型：
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作者：
Vansell,NicholeR;Klaassen,CurtisD
据推测，UDP-葡萄糖醛酸基转移酶(UGT)的诱导剂通过增加胆汁排泄量来降低循环中的甲状腺激素浓度。诱导剂孕烯醇酮-16α-碳腈(PCn)、3-甲基胆蒽(3MC)和芳氯苯1254(PCb)均能有效降低血清甲状腺激素浓度。然而，只有PCN治疗能显著增加血清促甲状腺激素(TSH)水平，而3MC和PCB治疗几乎不会引起TSH增加。TSH过度升高被认为是大鼠甲状腺肿瘤发生的主要刺激因素，然而酶诱导导致TSH升高的机制尚不完全清楚。在体外，PCN、3MC和PCB3种药物都能增加微粒体对T4的UGT活性，但只有PCN能引起T3-UGT活性的增加。本研究的目的是确定PCN升高血清TSH是否导致体内T3的葡萄糖糖醛酸化和胆汁排泄增加。雄性大鼠喂饲对照饲料或含有PCN(1000ppm)、3mc(250ppm)或PCb(100ppm)的饲料7天。然后给动物静脉注射[125I]-T3，收集胆汁2小时，用反相高效液相色谱结合γ检测胆汁中放射性标记的代谢物。PCN可使胆汁总放射性排泄量增加75%，但不增加3mc或PCB值。在排泄到胆汁中的T3中，大约75%以T3-葡萄糖醛酸苷的形式被回收，其余的数量表示为T3-硫酸盐、T2-硫酸盐、T3和T2。PCN可使胆汁中T_3-葡萄糖醛酸苷的排泄量增加66%，而3MC和PCB均不能改变T_3-葡萄糖醛酸苷的排泄。提示PCN可促进体内T3的葡萄糖糖醛酸化和胆汁排泄，提示促进T3的清除可能是PCN引起血清TSH升高的机制之一。
It has been postulated that inducers of UDP-glucuronosyltransferase (UGT) decrease circulating thyroid hormone concentrations by increasing their biliary excretion. The inducers pregnenolone-16α-carbonitrile (PCN), 3-methylcholanthrene (3MC), and Aroclor 1254 (PCB) are each effective at reducing serum thyroxine concentrations. However, only PCN treatment produces a marked increase in serum levels of thyroid-stimulating hormone (TSH), whereas 3MC and PCB cause little to no increase in TSH. Excessive TSH elevation is considered the primary stimulus for thyroid tumor development in rats, yet the mechanism by which enzyme induction leads to TSH elevation is not fully understood. Whereas PCN, 3MC, and PCB all increase microsomal UGT activity toward T4, only PCN causes an increase in T3-UGT activityin vitro. The purpose of this study was to determine whether PCN, which increases serum TSH, causes an increase in the glucuronidation and biliary excretion of T3in vivo. Male rats were fed control diet or diet containing PCN (1000 ppm), 3MC (250 ppm), or PCB (100 ppm) for 7 days. Animals were then given [125I]-T3, iv, and bile was collected for 2 h. Radiolabeled metabolites in bile were analyzed by reverse-phase HPLC with γ-detection. The biliary excretion of total radioactivity was increased up to 75% by PCN, but not by 3MC or PCB. Of the T3excreted into bile, approximately 75% was recovered as T3-glucuronide, with remaining amounts represented as T3-sulfate, T2-sulfate, T3, and T2. Biliary excretion of T3-glucuronide was increased up to 66% by PCN, while neither 3MC nor PCB altered T3-glucuronide excretion. These findings indicate that PCN increases the glucuronidation and biliary excretion of T3in vivo, and suggest that enhanced elimination of T3may be the mechanism responsible for the increases in serum TSH caused by PCN.