Thyroid cells

Figure 42-11. Model of iodide metabolism in the thyroid follicle. A follicular cell is shown facing the follicular lumen (top) and the extracellular space (at bottom). Iodide enters the thyroid primarily through a transporter (bottom left). Thyroid hormone synthesis occurs in the follicular space through a series of reactions, many of which are peroxidase-mediated. Thyroid hormones, stored in the colloid in the follicular space, are released from thyroglobulin by hydrolysis inside the thyroid cell. (Tgb, thyroglobulin MIT, monoiodotyrosine DIT, diiodotyro-sine Tj, triiodothyronine T4, tetraiodothyronine.) Asterisks indicate steps or processes that are inherited enzyme deficiencies which cause congenital goiter and often result in hypothyroidism.

The thyroid hormones thyroxine (T4) and triiodothyronine (T3) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell. Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine residues of thyroglobulin. 

Thyroid hormone is liberated into the bloodstream by the process of proteolysis within thyroid cells. T4 and T3 are transported in the bloodstream by three proteins thyroid-binding globulin, thyroid-binding prealbumin, and albumin. Only the unbound (free) thyroid hormone is able to diffuse into the cell, elicit a biologic effect, and regulate thyroid-stimulating hormone (TSH) secretion from the pituitary. 

In Graves disease, hyperthyroidism results from the action of thyroid-stimulating antibodies (TSAb) directed against the thyrotropin receptor on the surface of the thyroid cell. These immunoglobulin G antibodies bind to the receptor and activate the enzyme adenylate cyclase in the same manner as TSH. 

The goal of therapy is to destroy overactive thyroid cells, and a single dose of 4,000 to 8,000 rad results in a euthyroid state in 60% of patients at 6 months or less. A second dose of RAI should be given 6 months after the first RAI treatment if the patient remains hyperthyroid. 

Nishida M, Muraoka K, Nishikawa K, Takagi T, Kawada J (1989) Differential effects of methybnercuric chloride and mercuric chloride on the histochemistry of rat thyroid peroxidase and thyroid peroxidase activity of isolated pig thyroid cells. J Histochem Cytochem 37 723-727... 

Radio-iodine, I, diffusely kills thyroid cells resulting in eventual and inevitable hypothyroidism which often makes substitution with thyroxine necessary. Administered as capsules it is an effective oral treatment for hyperthyroidism. Patient should not be pregnant or become pregnant in the month following treatment. Breast-feeding is contraindicated. Painful radiation thyroiditis may occur. 

The thyroidal mechanism used for concentrating 1 may also concentrate other monovalent anions, including pertechnetate, perchlorate, and thiocyanate, within the follicular lumen. However, none of these anions become incorporated into Tg, although they may act as a competitive inhibitor of 1 transport. The ability of the thyroid gland to concentrate radioactive pertechnetate makes it a useful agent for thyroid imaging, since it is concentrated by the thyroid cells without further metabolism. The perchlorate and thiocyanate discharge tests make use of the ability of these anions to inhibit 1 transport to test for defects in the incorporation of 1 into Tg. 

Control of thyroid function via thyroid-pituitary feedback is also discussed in Chapter 37. Briefly, hypothalamic cells secrete thyrotropin-releasing hormone (TRH) (Figure 38-3). TRH is secreted into capillaries of the pituitary portal venous system, and in the pituitary gland, TRH stimulates the synthesis and release of thyrotropin (thyroid-stimulating hormoneTSH). TSH in turn stimulates an adenylyl cyclase-mediated mechanism in the thyroid cell to increase the synthesis and release of T4 and T3. These thyroid hormones act in a negative feedback fashion in the pituitary to block the action of TRH and in the hypothalamus to inhibit the synthesis and secretion of TRH. Other hormones or drugs may also affect the release of TRH or TSH. 

Graves disease is considered to be an autoimmune disorder in which helper T lymphocytes stimulate lymphocytes to synthesize antibodies to thyroidal antigens. The antibody described previously (TSH-R Ab [stim]) is directed against the TSH receptor site in the thyroid cell membrane and has the capacity to stimulate growth and biosynthetic activity of the thyroid cell. Spontaneous remission occurs but some patients require years of antithyroid therapy. 

Dysidenin (419) has been shown to have inhibition activity of the iodide transfer in thyroid cells through a different mechanism than ouabain [332]. Dysideathiazoles (420-424) were strongly deterrent in fish-feeding experiments [326] and barbamide (426) has shown molluscicidal activity [328]. 

Thyroid cells actively transport iodine (I-), which is incorporated into a few tyrosine residues of thyroglobulin by the enzyme iodoperoxidase. After condensation of iodinated tyrosine residues, the thyroglobulin is proteolytically degraded liberating thyroxine and triiodothyronine. 

Radioactive isotopes of iodine are handled by the thyroid in the same way as stable iodine and are therefore actively concentrated, incorporated into thyroglobulin, stored, metabolized, and secreted as thyroid hormones. Small amounts of radioactive iodine are therefore ideal probes to analyse the uptake of iodine, the distribution of iodine in the gland, and possibly even its turnover and incorporation into thyroid hormones. Larger amounts of radioactive iodine selectively radiate the thyroid gland and therefore selectively impair the function of the follicular thyroid cells and eventually destroy them. 

Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE, Boeynaems JM (1994) Inhibition of H202 Production by Iodoaldehydes in Cultured Dog Thyroid Cells. Mol Cell Endocrinol 102 167... 

Van Sande J, Deneubourg F, Beauwens R, Braekman JC, Daloze D, Dumont JE (1990) Inhibition of Iodide Transport in Thyroid Cells by Dysidenin, a Marine Toxin, and Some of Its Analogs. Mol Pharmacol 37 583... 

The primary steps in thyroid hormone biosynthesis are shown schematically in Figure 31-2. Thyroid follicle cells take up and concentrate iodide from the bloodstream—this is significant because there must be a sufficient amount of iodine in the diet to provide what is needed for thyroid hormone production.55 Thyroid cells also manufacture a protein known as thy-... 

Iodide. Relatively large dosages of iodide (exceeding 6 mg/d) cause a rapid and dramatic decrease in thyroid function.35 In sufficient amounts, iodide inhibits virtually all the steps involved in thyroid hormone biosynthesis. For instance, high iodide levels limit the uptake of iodide into thyroid follicle cells, inhibit the formation of T4 and T3, and decrease the secretion of the completed hormones from the thyroid cell. 

Pacifico, F., Montuori, N., Mellone, S., et al. (2003) The RHL-1 subunit of the asialoglycoprotein receptor of thyroid cells cellular localization and its role in thyroglobulin endocytosis. Mol. Cell. Endocrinol. 208(1-2), 51-59. 

Small lipophilic (lipid-soluble) hormones diffuse across the plasma membrane and then interact with intracellular receptors in the cytosol or nucleus. The resulting hormone-receptor complex often binds to regions of the DNA and affects the transcription of certain genes (see Topic G7). Small lipophilic hormones with intracellular receptors include the steroid hormones which are synthesized from cholesterol (see Topic K5) (e.g. the female sex hormones estrogen and progesterone), thyroxine which is produced by thyroid cells and is the principal iodinated compound in animals, retinoic acid which is derived from vitamin A, and vitamin D which is synthesized in the skin in response to sunlight (see Topic K5). 

Intermediate-duration oral studies in rats have shown that high doses of DEHP can affect thyroid cell structure (e g., hypertrophy of Golgi apparatus, increases in lysosomes, dilation of the endoplasmic reticula, and increase in colloid droplets) and function (e.g., decrease levels of circulating T4) (Hinton et al. 1986 Poon et al. 1997 Price et al. 1987, 1988a). When large oral doses of 500 and 2,500 mg/kg/day DEHP were combined with dietary exposure to a compound which has similar effects on the thyroid (Aroclor 1254, a polychlorinated biphenyl mixture), there was an apparent additive effect of the two compounds on changes in thyroid cell structure and decreases in serum T3 and T4. At lower doses of DEHP (50 and 100 mg/kg/day) and Aroclor 1254 there were no additive effects apparent with the changes in cell structure or the levels of T3 and T4. 

Tamir H, Hsiung SC, Yu PY, et al. Serotonergic signalling between thyroid cells protein kinase C and 5-HT2 receptors in the secretion and action of serotonin. Synapse 1992 12 155-168. 

Iodide Thyroid cells Bagchi Fawcett (1973). Biochim. Biophys. Acta 318, 235-251. 

The leading cause of Graves disease occurs when there is a defect in the immune system that causes the production of autoantibodies to TSH receptors located on the surface of thyroid cells. These antibodies act as agonists to stimulate the thyroid, causing it to enlarge (goiter formation), with the overproduction of thyroid hormones... 

Ragno P, Montuori N, Covelli B, Hoyer-Hansen G, Rossi G. Differential expression of a truncated form of the urokinase-type plasminogen-activator receptor in normal and tumor thyroid cells. Cancer Res 1998 58(6) 1315—1319. 

Montuori N, Rossi G, Ragno P. Cleavage of urokinase receptor regulates its interaction with integrins in thyroid cells. FEBS Lett 1999 460(l) 32-36. 

Paron I, D Ambrosio C, Scaloni A, Berlingieri MT, Pallante PL, Fusco A, et al. A differential proteomic approach to identify proteins associated with thyroid cell transformation. J Mol Endocrinol 2005 34(1) 199-207. 

The response of mast cells includes release of arachidonic acid due to membrane PhL A2 activation following a ligand-induced increase in cellular Ca2+. PTX reduces the Ca2+-mediated GTP S-dependent release of this fatty acid in permeabil-ized cells [102,103]. This raised the possibility of a direct link, not only between receptors and PhL C, but also between receptors and PhL A2. Existence of a G protein-mediated. PTX-sensitive, activation of PhL A2 independent of G protein-mediated activation of PhL C was confirmed in studies first with fibroblasts [104] and then with FRTL thyroid cells [105]. Studies with the latter cells show that a,-adrenergic receptors promote arachidonic acid release [105] and that this effect is mimicked in permeabilized cells by GTP and is not blocked by inhibition of PhL C with neomycin. Thus, at least two Gp proteins need to be defined a Gp-stimu-lating PhL C (Gp(c) and a Gp-stimulating PhL A2 (Gp,a). It is possible that rat brain G is PTX-sensitive Gplc. 

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