The resurgence of the clinical use of perchlorate as a means of controlling amiodarone-induced thyroid dysfunction has suggested a need for a more careful examination of the actions of this antithyroid anion. To accomplish this, it is essential to understand the chemical, biochemical, and

Perchlorate and the Thyroid Gland

Iodide transport in the thyroid gland.

Publisher Summary This chapter discusses the action of thyrotropin on thyroid metabolism. Growth and function of the thyroid are mainly controlled by the level of thyrotropin (TSH) concentration in the plasma. The principal element of this control, the action of TSH on its target, the thyroid follicular cell, has been investigated intensively during recent years. TSH activates rapidly the steps of thyroidal iodine metabolism—that is, the formation of thyroid hormones from iodide and tyrosines and the secretion of these hormones, and induces, after a delay, the growth of thyroid tissue. Among the various systems available for the study of the interaction of a tropic hormone with its target cell, the thyroid and TSH present several advantages and disadvantages. The specialized metabolism of the follicular cell, the metabolism of iodine, is easily studied with the various radioisotopes of iodine. Thyroid tissue is very resistant to adverse conditions, which explains the great stability and the great variety of in vitro thyroid systems.

The action of thyrotropin on thyroid metabolism.

To investigate the mechanism of I- transport stimulation by TSH, we studied the effects of TSH on Na+/I- symporter (NIS) messenger RNA (mRNA) and protein levels in FRTL-5 cells and correlated these with I- transport activity. When 1 mU/ml TSH was added to quiescent FRTL-5 cells, a 12-h latency was observed before the onset of increased I- transport activity, which reached a maximum [approximately 27 times basal (5H medium) levels] at 72 h. In contrast, Northern blot analysis, using rat NIS complementary DNA as a probe, revealed that addition of TSH to these cells significantly increased NIS mRNA at 3-6 h, reaching a maximum after 24 h (approximately 5.9 times basal levels). Forskolin and (Bu)2cAMP mimicked this stimulatory effect on both the I- transport activity and mRNA levels. D-ribofranosylbenzimidazole, a transcription inhibitor, almost completely blocked TSH-induced stimulation of I- transport and NIS mRNA levels. Western blot analysis demonstrated that TSH increased NIS protein levels at 36 h, reaching a maximum at 72 h, in parallel with the kinetics of TSH-induced I- transport activity. However, it also showed that the amount of NIS protein already present in FRTL-5 cell membranes before the addition of TSH was about one third of the maximum level induced by TSH. These results indicate that stimulation of I- transport activity by TSH in thyrocytes is partly due to a rapid increase in NIS gene expression, followed by a relatively slow NIS protein synthesis. However, the existence of an abundant amount of protein in quiescent FRTL-5 cells with very low I- transport activity also suggests that this activity is controlled by another TSH-regulated factor(s).

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Regulation by thyroid-stimulating hormone of sodium/iodide symporter gene expression and protein levels in FRTL-5 cells.

This chapter has outlined the complex process required for thyroid growth and function. Both events are regulated by TSHR via a multiplicity of signals, with the aid of and requirement for a multiplicity of hormones that regulate the TSHR via receptor cross-talk: insulin, IGF-I, adrenergic receptors, and purinergic receptors. Cross-talk appears to regulate G-protein interactions or activities induced by TSH as well as TSHR gene expression. The TSHR structure and its mechanism of signal transduction is being rapidly unraveled in several laboratories, since the recent cloning of the receptor. In addition, the epitopes for autoantibodies against the receptor that can subvert the normal regulated synthesis and secretion of thyroid hormones, causing hyper- or hypofunction, have been defined. Studies of regulation of the TSHR minimal promotor have uncovered a better understanding of the mechanisms by which TSH regulates both growth and function of the thyroid cell. A key novel component of this phenomenon involves TSH AMP positive and negative regulation of the TSHR. Negative transcriptional regulation is a common feature of MHC class I genes in the thyroid. Subversion of negative regulation or too little negative regulation is suggested to result in autoimmune disease. Methimazole and iodide at autoregulatory levels may be important in reversing this process and returning thyroid function to normal. Their action appears to involve factors that react with the IREs on both the TSHR and the TG promoter. Too much negative regulation, as in the case of ras transformation, results in abnormal growth without function. TTF-1 is implicated as a critical autoregulatory component in both positive and negative regulation of the TSHR and appears to be the link between TSH, the TSHR, TSHR-mediated signals, TG and TPO biosynthesis, and thyroid hormone formation. Differentially regulated expression of the TSHR and TG by cAMP and insulin depend on differences in the specificity of the TTF-1 site, that is, the lack of Pax-8 interactions with the TSHR, and the IRE sites. Single-strand binding proteins will become important in determining how TSHR transcription is controlled mechanistically.

The thyrotropin receptor.

Assessing the activity of the thyroidal iodide pump by measuring the thyroid/serum radioiodide gradient (T/S), we found the stimulatory effect of TSH to have a latency of from about 8 hours to 12 hours or more. The longer latent periods were observed in rats whose initial T/S was relatively high. The rise in the T/S was preceded by a depression of this ratio, whether hypophysectomized, normal, or triiodothyronine (T3) treated rats were injected with TSH. This biphasic response was elicited with Armour TSH, lyophilized rat pituitary tissue and Bates' highly purified mouse tumor and bovine TSH preparations; it seems therefore reasonable to attribute it to TSH proper rather than some contaminant(s). The same kind of response was also observed in rats whose thyroids were purged of organic iodine with goitrogens and whose endogenous TSH output was subsequently inhibited by giving T3 along with the antithyroid drugs; this indicates that the initial depression of the T/S is not due to flooding of the thyroidal i...

Biphasic effect of TSH on thyroidal iodide collection in rats.

Equilibration of radioiodide between thyroid and blood was studied in rats fed propylthiouracil with or without subsequent acute administration of thiocjanate, stable iodide or perchlorate. The results were analyzed in terms of Wollman and Reed's open two-compartment model of the thyroidal iodide pump. All three anions examined were found to inhibit thyroidal radioiodide collection predominantly through lowering of the unidirectional clearance of plasma radioiodide by the thyroid, and to a lesser extent by enhancing the exit rate constant of thyroidal radioiodide. These observations are scrutinized for information regarding the anatomical site of the thyroidal iodide pump.

B. H. Peters

Papers

Biphasic effect of TSH on thyroidal iodide collection in rats.

[Effect of thiocyanate, stable iodide and perchlorate on the kinetics of radioiodide transport between thyroid gland and blood of rats].