Thyroxine actions

When it was suggested that the uneoiipling of oxidative phosphorylation induced by thyroxine is probably a result of its effect on the stnuiture of mitochondria (Tapley, l<)b()), t wo major objections prevented a consideration of thmitochondrial membrane might be the in vivo lo( ns of thyroxine action. First, the effect on mitochondria could be produced by thyroxine analogs of low in vivo potency for example, both... 

Gallagher and co-workers [389] have emphasized that metabolites of corticoid hormones are not simply inactive end-products of a spent hormone ready for elimination, but may have their own important metabohc functions. Thus, androsterone, an end-metabohte of androgens, is an effective endogenous hypocholesterolemic hormone. Moreover, the production of androsterone is increased as one of the results of thyroxine action hence, this androgen meta-... 

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). 

Amphibians. Amphibians are highly susceptible to endocrine disruption during development of the larval form and during metamorphosis. The action of metamorphosis is triggered and controlled by the thyroid gland via an increase in triiodothyronine and a decrease in thyroxine, and differs greatly between oviparous and viviparous species. Experimentally, it has been shown that disruption during this sensitive period can lead to malformations and adverse impacts on immune and reproductive functions. 

Propylthiouracil (PTU), but not methyl-mercaptoi-midazole (MMI), has an additional peripheral effect. It inhibits the monodeiodination of thyroxine to triiodothyronine by blocking the enzyme 5 mono-deiodinase [1]. In humans the potency of MMI is at least 10 times higher than that of PTU, whereas in rats PTU is more potent than MMI. The higher potency of MMI in humans is probably due to differences in uptake into the thyroid gland and subsequent metabolism, because in vitro inhibition of thyroid peroxidase by MMI is not significantly more potent than by PTU [1, 6]. Whether antithyroid drags have additional immunosuppressive actions is a matter of discussion [1, 2]. 

Particular attention is given to the development of new mechanistic biomarker assays and bioassays that can be used as indices of the toxicity of mixtures. These biomarker assays are typically based on toxic mechanisms such as brain acetylcholinesterase inhibition, vitamin K antagonism, thyroxin antagonism, Ah-receptor-mediated toxicity, and interaction with the estrogenic receptor. They can give integrative measures of the toxicity of mixtures of compounds where the components of the mixture share the same mode of action. They can also give evidence of potentiation as well as additive toxicity. 

Like steroid hormones, thyroid hormones interact with receptors to alter genomic activity and affect the synthesis of specific proteins during development [25-28], As with testosterone and progesterone, metabolic transformation of thyroxine (T4) is critical to its action [25-28]. Moreover, as with steroid hormones, thyroid hormones alter brain functions in adult life in ways that both resemble and differ from their action during development [25-28]. 

Figure 1.5 The thyroid hormones thyroxine and triiodothyronine are produced by the action of iodoperoxidase and subsequent proteolysis of thyroglobin. (From Voet and Voet, 2004. Reproduced with permission from John Wiley Sons., Inc.)...

Calcium is the major mineral component of bone and normal repair and remodelling of bone is reliant on an adequate supply of this mineral. Calcium uptake in the gut, loss through the kidneys and turnover within the body are controlled by hormones, notably PTH and 1,25 dihydroxy cholecalciferol (1,25 DHCC or 1,25 dihydroxy vitamin D3 or calcitriol). Refer to Figure 8.12 for a summary of the involvement of PTH and vitamin D3 in controlling plasma calcium concentration. These two major hormones have complementary actions to raise plasma calcium concentration by promoting uptake in the gut, reabsorption in the nephron and bone resorption. Other hormones such as thyroxine, sex steroids and glucocorticoids (e.g. cortisol) influence the distribution of calcium. 

The Class III effects of amiodarone develop over several weeks. This time-course is similar to that seen in thyroid gland ablation [25]. It is well known that patients with hypothyroidism have long QT intervals which are indicative of prolonged action potentials. Amiodarone has been shown to inhibit the conversion of thyroxine (T4) to triiodothyronine (T3) both in human subjects [26] and in vitro [27]. It has been argued that the Class III effects of amiodarone are due to its effects on thyroid hormones [28]. Others, however, argue that there is no relationship between prolongation of ventricular refractory period by amiodarone and thyroid state [29]. 

Z)-2,3-Methanothyronine 59 and its dibromo derivative 60 have comparable activity with the thyroxine 61, a thyroid hormone [66], which exhibited thyro-mimetic activities in basal metabolism and antigoiter tests (comparison of oxygen consumption and heart rate in normal and thyroidectomized rats) but did not have an inhibitory action on the metabolism developed by triiodothyronine [66]. (Z)-2,3-Methanohistidine 62, tested on rat liver, is an effective inhibitor of histidine decarboxylase, Eq. (23) [67]. 

Parenterally it is indicated in the management of myxedema coma or when thyroxine cannot be given orally. Onset of action occurs within a few hours and its activity lasts for some days after withdrawal of therapy. 

Mechanism of Action Asynfheficisomer of thyroxine involved in normal metabolism, growth, and development, especially of fhe CNS in infants. Possesses catabolic and anabolic effects. Therapeutic Effect Increases basal metabolic rate, enhances gluco-neogenesis and stimulates protein synthesis. 

Mecfianism of Action A thiourea derivative that blocks oxidation of iodine in the thyroid gland and blocks synthesis of thyroxine and triiodothyronine. Therapeutic Effect Inhibits synthesis of thyroid hormone. 

It also inhibits ADH action on distal tubules (diabetes insipidus like state), also has insulin like action on glucose metabolism and decreases thyroxine synthesis by interfering with iodination of thyroxine. 

There is no final consensus on whether normal use of lithium, without any episode of toxicity (the vast majority of patients), may result in permanent renal impairment. Polyuria occurs in 20-40% and is due to inhibition of antidiuretic hormone (ADH) by lithium. It usually resolves on cessation of lithium as do any effects on glomerular function. Interference with thyroid function is due to inhibition of the action of thyroid stimulating hormone (TSH) and is easily managed by administration of thyroxine. Lithium is contraindicated during pregnancy (major vessel anomalies in fetus) and breastfeeding. 

Excessive catecholamine action is an important aspect of the pathophysiology of hyperthyroidism, especially in relation to the heart (see Chapter 38). The 13 antagonists are beneficial in this condition. The effects presumably relate to blockade of adrenoceptors and perhaps in part to the inhibition of peripheral conversion of thyroxine to triiodothyronine. The latter action may vary from one 13 antagonist to another. Propranolol has been used extensively in patients with thyroid storm (severe hyperthyroidism) it is used cautiously in patients with this condition to control supraventricular tachycardias that often precipitate heart failure. 

Dronedarone is a structural analog of amiodarone and lacks iodine atoms. The design was intended to eliminate action of the parent drug on thyroxine metabolism and to modify the half-life of the drug. Dronedarone has multiple actions like amiodarone, blocking IKr, IKs, ICa, INa, and adrenoceptors. The drug has a half-life of 24 hours and was administered twice daily in the initial clinical trials. No thyroid or pulmonary toxicity has been noted during early use. 

Albumin is the most abundant protein in human and other animal plasma. It is estimated that up to 40% of the total albumin in humans is in circulation transporting essential nutrients, especially those that are sparingly soluble in aqueous-based plasma. For example, the fatty acids, which are important fuel molecules for the peripheral tissue, are distributed by albumin. In addition, albumin is the plasma transport protein for other substances including bilirubin, thyroxine, and steroid hormones. Also, many drugs including aspirin, sulfanilamides, clofibrate, and digitalis bind to albumin and are most likely carried to their sites of action by the protein. 

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