Thyroidal hormone

Brent et al., 1989] Brent, G. A., Dunn, M. K., Harney, J. W., Gulick, T., and Larsen, P. R. Thyroid hormone aporeceptor represses Ta inducible promoters and blocks activity of the retinoic acid receptor. New Biol. 1 (1989) 329-336 [Cevc and Marsh, 1987] Cevc, G., and Marsh, D. Phospholipid Bilayers Physical Principles and Models. John Wiley Sons, New York, 1987. 

Thyroid compounds Thyroid counter Thyroid gland Thyroid hormone... 

Amino acid-derived hormones include the catecholamines, epinephrine and norepinephrine (qv), and the thyroid hormones, thyroxine and triiodothyronine (see Thyroid AND ANTITHYROID PREPARATIONS). Catecholamines are synthesized from the amino acid tyrosine by a series of enzymatic reactions that include hydroxylations, decarboxylations, and methylations. Thyroid hormones also are derived from tyrosine iodination of the tyrosine residues on a large protein backbone results in the production of active hormone. 

Thyroid-stimulating hormone can be used clinically to test thyroid function but has not found practical apphcation in the treatment of human thyroid insufficiency. Direct replacement therapy with thyroid hormone is easy and effective, owing to a simple molecular stmcture. TSH has been used in the veterinary treatment of hypothyroidism, and preparations of TSH ate produced by Cooper Animal Health, Inc. and Armour Pharmaceuticals. 

Metabolic Functions. The functions of the thyroid hormones and thus of iodine are control of energy transductions (121). These hormones increase oxygen consumption and basal metaboHc rate by accelerating reactions in nearly all cells of the body. A part of this effect is attributed to increase in activity of many enzymes. Additionally, protein synthesis is affected by the thyroid hormones (121,122). 

Thyroid Hormones. Iodine, absorbed as P, is oxidized in the thyroid and bound to a thyroglobulin. The resultant glycoprotein, mol wt 670,000, contains 120 tyrosine residues of which ca two-thirds are available for binding iodine in several ways. Proteolysis introduces the active hormones 3,5,3 -triiodothyronine (T ) and 3,5,3, 5 -tetraiodothyronine (T, (thyroxine) in the ratio Ty.T of 4 1 (121,122). 

Only small amounts of free T are present in plasma. Most T is bound to the specific carrier, ie, thyroxine-binding protein. T, which is very loosely bound to protein, passes rapidly from blood to cells, and accounts for 30—40% of total thyroid hormone activity (121). Most of the T may be produced by conversion of T at the site of action of the hormone by the selenoenzyme deiodinase (114). That is, T may be a prehormone requiring conversion to T to exert its metaboHc effect (123). 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Thyroid hormone receptors (THRs) are subdivided intoa and P types, each having two isoforms. In rat brain, THR, mRNA is present in hippocampus, hypothalmus, cortex, cerebellum, and amygdala. Thyroxine (l-T (284) and triiodothyronine (l-T ) (285) are endogenous ligands for the THRs. TRIAC (286) is a THR antagonist. Selective ligands for PPARs have yet to be identified (Table 16). 

The main role of the human thyroid gland is production of thyroid hormones (iodinated amino acids), essential for adequate growth, development, and energy metaboHsm (1 6). Thyroid underfunction is an occurrence that can be treated successfully with thyroid preparations. In addition, the thyroid secretes calcitonin (also known as thyrocalcitonin), a polypeptide that lowers excessively high calcium blood levels. Thyroid hyperfunction, another important clinical entity, can be corrected by treatment with a variety of substances known as antithyroid dmgs. 

Fig. 1. Mechanisms controlling free thyroid-hormone levels.

Fig. 2. Early events in thyroid-hormone action. Interaction of T with cell nuclear receptors (6).

Myxedema and goiter are the main conditions for which thyroid preparations are indicated. The treatment of cretinism is difficult because it is recognized only at or after birth. Even if this disease could be diagnosed m utero, thyroid hormones do not readily cross the placental barrier. In addition, the fetus, as does a premature infant, rapidly deactivates the thyroid hormones. The halogen-free analogue DlMlT [26384-44-7] (3), which is resistant to fetal deiodinases, may prove useful for fetal hypothyroidism (cretinism). 

Structure—Activity Relationships. In spite of the considerable synthetic and bioassay effort involved in estabhshing the thyromimetic potency of thyroid-hormone analogues, more than 100 compounds have been studied (Table 2). The main stmctural requirements for thyromimetic activity can be summarized as follows (6,12—16). 

Chemical Assay. In view of the similarity of their chemical and physical properties (see Table 1) (29), the main problem in the chemical analysis of the thyroid hormones is their separation. A USP procedure gives the details of a paper chromatographic separation in which T is examined for contamination by T and 3,5-diiodothyroiiine (30). Other systems are also employed (29). 

The amphibian metamorphosis test is based on the abiUty of thyroid hormones to induce precocious transformation of a tadpole into a frog or of the axolod into a salamander. It is rarely used because of solubiUty problems and the difficulty of applying the results to humans. 

Using any of the carrier proteins available in highly purified form, eg, TBG or TBPA, a convenient and accurate quantitative determination of and is possible by displacement of radioiodinated or T. This procedure enables their quick determination at low concentrations even in the presence of coundess other substances that occur in body duids (31). In a similar fashion, intact cell nuclei or solubilized proteins from rat fiver cell nuclei, which display high affinities for thyroid hormones, especially T, have been used to establish relative binding affinities of many thyromimetic compounds (7). 

Iodide and Other Inorganic Anions. When large doses of iodide ion are administered, a transient inhibition of synthesis and release of the thyroid hormones is brought about by the so-called Wolff-Chaikoff effect. 

Thiocyanate ion, SCN , inhibits formation of thyroid hormones by inhibiting the iodination of tyrosine residues in thyroglobufin by thyroid peroxidase. This ion is also responsible for the goitrogenic effect of cassava (manioc, tapioca). Cyanide, CN , is liberated by hydrolysis from the cyanogenic glucoside finamarin it contains, which in turn is biodetoxified to SCN. 

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