Dual mechanisms of regulation of type I iodothyronine 5'-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.
Dual mechanisms of regulation of type I iodothyronine 5'-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.
复制标题
大鼠肾、肝和甲状腺中 I 型碘甲状腺原氨酸 5-脱碘酶的双重调节机制。
DOI：
10.1172/jci113479
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
StGermain,DL
中科院分区：
文献类型：
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作者：
StGermain,DL
甲状腺激素状态的改变和放射造影剂的使用可显著影响碘甲腺原氨酸代谢，特别是I型5 '-脱碘酶（5' DI）的活性。在目前的研究中，对这些影响的机制进行了重新评估。如前所述，向破碎的细胞制备物中加入碘番酸（IOP）导致5 'DI抑制的竞争性模式。然而，大鼠体内给予IOP或3，3 '，5'-三碘甲腺原氨酸（rT 3）导致肝脏、肾脏和甲状腺中5 'DI的非竞争性抑制模式，由此注意到最大酶速度（Vmax）显著降低，而Michaelis-Menten常数值无变化。在注射3，5，3 '-三碘甲状腺原氨酸（T3）导致甲状腺功能亢进的大鼠中，肝脏和肾脏中的5' DI活性显着增加。对这些甲状腺毒性动物给予IOP导致酶活性迅速丧失，其特征在于两种组织中的5 'DI V max值降低约80%。此外，在单次IOP注射后，这种抑制作用持续超过60小时。IOP给药还使甲状腺中的5 'DIVmax水平降低了52%。在其他实验中，用IOP或rT 3处理完整的Escherber FAO肝癌细胞诱导5 'DIV max水平的快速降低。在用放线菌酮处理的细胞中，这些试剂使酶活性消失的速率提高了12倍以上，表明对加速酶失活和/或降解的速率具有显著作用。这些研究表明，碘甲腺原氨酸和其他碘化化合物对5 'DI具有复杂的调节作用，这需要改变酶的活化和失活速率。以前接受的概念，rT 3和IOP损害甲状腺素（T4）的T3转换在体内作为竞争性抑制剂是一个过于简单化。相反，对甲状腺功能亢进症患者给予这些药物的临床有益作用可能主要是由于甲状腺和外周组织中发生的5 'DI的快速和长期失活。
Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.