Thyroid hormones mechanism

Thyroid hormone mechanisms of action can be classified into two types (1) genomic or nuclear and (2) nongenomic, including effects at the plasma membrane and mitochondria. Genomic effects involve modification of gene transcription, are mediated only by Tj, and require at least several hours to detect. Nongenomic actions are generally rapid in onset and occur in response to T4 and some T4 metabolites (e.g., rT3,T3, and Tj). 

Steroid and Thyroid Hormone Mechanisms The Insulin Receptor... 

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

Brouwer, A., Morse, D.C., and Lans, M.C. et al. (1998). Interactions of persistent enviromnen-tal organohalogens with the thyroid hormone system Mechanisms and possible conse-qnences for animal and hnman health. Toxicology and Industrial Health 14, 59-84. 

The amino acid tyrosine is the starting point in the synthesis of the catecholamines and of the thyroid hormones tetraiodothyronine (thyroxine T4) and triiodothyronine (T3) (Figure 42-2). T3 and T4 are unique in that they require the addition of iodine (as T) for bioactivity. Because dietary iodine is very scarce in many parts of the world, an intricate mechanism for accumulating and retaining T has evolved. 

The thyroid hormones T3 and T4 are unique in that iodine (as iodide) is an essential component of both. In most parts of the world, iodine is a scarce component of soil, and for that reason there is htde in food. A complex mechanism has evolved to acquire and retain this cmcial element and to convert it into a form suitable for incorporation into organic compounds. At the same time, the thyroid must synthesize thyronine from tyrosine, and this synthesis takes place in thyroglobuhn (Figure 42-11). 

Liu R, Li Z, Bai S, et al. Mechanism of cancer cell adaptation to metabolic stress proteomics identification of a novel thyroid hormone-mediated gastric carcinogenic signaling pathway. Mol. Cell. Proteomics 2009 8 70-85. 

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

Reports of the effects of Li+ upon the thyroid gland and its associated hormones are the most abundant of those concerned with the endocrine system. Li+ inhibits thyroid hormone release, leading to reduced levels of circulating hormone, in both psychiatric patients and healthy controls [178]. In consequence of this, a negative feedback mechanism increases the production of pituitary TSH. Li+ also causes an increase in hypothalamic thyroid-releasing hormone (TRH), probably by inhibiting its re-... 

The concentration of Li+ in the thyroid is three to four times that in serum [179]. It is thought that Li+ may be concentrated in the thyroid gland by a mechanism similar to the incorporation of iodide, I-, resulting in competition between Li+ and I the levels of intracellular 1 decrease when those of Li+ increase, and vice versa [182]. Li+ inhibits both the ability of the gland to accumulate 1 and the release of iodine from the gland. In vitro, Li+ has no effect on thyroid peroxidase, the enzyme that catalyzes the incorporation of I" into tyrosyl residues leading to thyroidal hormone synthesis, but does increase the activity of iodotyrosine-deio-dinase, which catalyzes the reductive deiodination of iodotyrosyls, thus maintaining the levels of intracellular I [182]. The increase in iodoty-rosine-deiodinase activity is probably a response to the Li+-induced decrease in the concentration of thyroidal I". Li+ has no effect on the conversion of thyroxine to triiodothyronine. The overall effect of this competition between Li+ and 1 is, therefore, reduced levels of thyroid hormone in the presence of Li+. 

Atrophy of the thymus is a consistent finding in mammals poisoned by 2,3,7,8-TCDD, and suppression of thymus-dependent cellular immunity, particularly in young animals, may contribute to their death. Although the mechanisms of 2,3,7,8-TCDD toxicity are unclear, research areas include the role of thyroid hormones (Rozman et al. 1984) interference with plasma membrane functions (Matsumura 1983) alterations in ligand receptors (Vickers et al. 1985) the causes of hypophagia (reduced desire for food) and subsequent attempts to alter or reverse the pattern of weight loss (Courtney et al. 1978 Seefeld et al. 1984 Seefeld and Peterson 1984) and excretion kinetics of biotransformed metabolites (Koshakji et al. 1984). 

TCDD also causes thyroid tumours in male rats. This has been shown to proceed through a mechanism that involves altered thyroid hormone metabolism and consequent increases in feedback mechanisms, TSH (thyroid stimulating hormone), which results in a chronic proliferative stimulation of thyroid follicular cells. 

Receptor-effector mechanisms include (1) enzymes with catalytic activities, (2) ion channels that gate the transmembrane flux of ions (ionotropic receptors), (3) G protein-coupled receptors that activate intracellular messengers (metabotropic receptors), and (4) cytosolic receptors that regulate gene transcription. Cytosolic receptors are a specific mechanism of many steroid and thyroid hormones. The ionotropic and metabotropic receptors are discussed in relevance to specific neurotransmitters in chapter 2. 

This does not mean that the thyroid hormones are normally detrimental to survival in starvation. Laboratory animals are protected from factors such as marked fluctuations in ambient temperature, the need to find food, and from predators such problems in the wild require the action of triiodothyronine, to increase the sensitivity of regulatory mechanisms to aid the response to such problems. High rates of energy expenditure are therefore, essential for survival in the wild ... 

Thyroid hormones accelerate metabolism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of thyroid hormones rises by means of this negative feedback mechanism, hormone production is automatically adjusted to demand. 

There are several ways by which TSH secretion can be increased. An increased hepatic enzyme activity may cause an increased metabolism of thyroid hormones, leading to lower semm hormone levels, which in mm leads to increased secretion of TRH, and subsequently increased TSH secretion. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-thyroid axis of rats and humans are similar and the mechanism is relevant for humans, but the human system is far more resistant to perturbation. 

The lARC has determined that there is sufficient evidence for the carcinogenicity of amitrole to experimental animals and inadequate evidence for carcinogenicity to humans. It was noted that amitrole produces thyroid tumors in rodents by a nongenotoxic mechanism that involves interference with the functioning of the thyroid peroxidase, resulting in a reduction in circulating thyroid hormone concentration and an increase secretion of thyroid-stimulating hormone. Amitrole would not be expected to produce thyroid cancer in humans exposed to concentrations that do not alter thyroid hormone homeostasis. 

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