Triiodothyronine physiology

A second dietary trace element, selenium, is also essential for normal thyroid hormone metabohsm. Selenium in the form of selenocysteine is a required component for three enzymes that remove iodide from thyroid hormones. Deiodination is the major metabohc pathway by which T4 and T3 are cleared from the system. After secretion by the thyroid gland, T4 may be deiodinated to yield either T3 or the physiologically inactive reverse Tj (3,3, 5 -triiodothyronine, or rX3). T3 and rTj are further deiodinated to form less active metabolites. Selenium, like iodine, is deficient in many areas of the world. 

Thyroid gland secretes two important hormones, thyroxine (TJ and triiodothyronine (Tj). The third hormone, calcitonin secreted from interstitial cells is physiologically different and is responsible for the regulation of calcium metabolism. 

Several studies have failed to confirm the benefits of combined levothyroxine and liothyroninc therapy. Liothyroninc given once a day results in non-physiologi-cal peak serum concentrations of T3. Modified-release triiodothyronine plus thyroxine can normalize serum biochemistry, but it is not known whether this formulation is superior to levothyroxine alone (15). 

Because thyroxine contains four iodine residues, this compound is also referred to by the abbreviation T4. Likewise, triiodothyronine contains three iodine residues, hence the abbreviation T3. There has been considerable discussion about which hormone exerts the primary physiologic effects. Plasma levels of T4 are much higher than T3 levels, but T3 may exert most of the physiologic effects on various tissues, which suggests that T4 is a precursor to T3 and that the conversion of T4 to T3 occurs in peripheral tissues.23 Regardless of which hormone ultimately affects cellular metabolism, both T4 and T3 are needed for normal thyroid function. 

Chopra IJ, Ho RS, Lam R (1972) An improved radioimmunoassay of triiodothyronine in serum its application to clinical and physiological studies. J Lab Clin Med 80 729-739... 

Selenium is an essential trace element, being important in at least two critical enzymes, the antioxidant glutathione peroxidase (GPx), and type 1 iodothyronine deiodinase. GPx converts hydrogen peroxide to water, in the presence of reduced glutathione, while iodothyronine deiodinase catalyzes the conversion of thyroxine to triiodothyronine, the physiologically active hormone species. 

Phenylalanine and tyrosine are also metabolized in higher organisms by two routes which are quantitatively less important but physiologically of the highest importance. The first leads to the adrenal hormones adrenaline (epinephrine) and noradrenaline (norepinephrine),which may be formed as in diagram 11 this pathway also leads to melanin (diagram 12). The second leads to the thyroid hormones thyroxine and triiodothyronine, the synthesis and breakdown of which are also discussed. 

Endocrine Effects. Selenium is a component of all three members of the deiodinase enzyme family, the enzymes responsible for deiodination of the thyroid hormones, and has a physiological role in the control of thyroid hormone levels. Significant decreases in triiodothyronine levels in response to elevated selenium have been observed in humans. However, the triiodothyronine levels observed in these studies were within the normal human range, so the biological impact of this change is unclear. 

The expression of the sodium iodide symporter is perhaps nowhere more important than in the thyroid gland. A complete review of the physiological importance of the thyroid is beyond the scope of this chapter. It is sufficient to say that the symporter provides the iodine needed for normal thyroid function. Once the symporter has been trafficked to the basolateral surface of the thyrocyte, it can transport iodine from the blood into the cell. Once inside the cells, iodine is transported to the apical membrane where it is organified through attachment to a tyrosine residue and incorporated into the thyroid hormone thyroglobulin. The thyroglobu-lin is then stored inside thyroid follicles as colloid, to be released into the bloodstream as thyroid hormones (thyroxine and triiodothyronine) via TSH stimulation. 

Mussett MV, Pitt-Rivers R. The physiologic activity of thyroxine and triiodothyronine analogs. Metab Clin Exper 1957 6 18-25. 

Addendum 1 (Section 2.3, p. Ill) Recently Chopra (C7a) demonstrated that 3,3, 5 -triiodothyronine or reverse Tj (rTa) is present in normal serum in a concentration of approximately 40 ng/100 ml and that there are large increases in rTa concentration in the serum of the newborn when serum Ta concentration is very low. As rTa has no physiological activity, he postulated that deiodination of T may switch from T, to rTa as regulatory mechanism controlling the biological action and metabolism of Ta. 

Dietary iodine is essential for the production of thyroid hormones, thyroxine and triiodothyronine, which regulate many important physiological processes in humans (Haldimann et ah, 2005). More than 1.9 billion individuals are estimated to have inadequate iodine nutrition the lowest iodine deficiency is in America and the highest in Europe (de Benoist et ah, 2003). 

Of the many thyroxine analogs which have been prepared in a chemically pure form and tested for physiological activity, relatively few have been detected in mammalian tissues. After the isolation of thyroxine in 1915, no other iodinated thyronines were discovered in thyroid tissue until after the advent of radioactive isotopes. 3,5, 3 -L-Triiodothyronine was isolated by Gross and Pitt-Rivers in 1952 and by Roche, Lissitzky, and Michel (1952). The finding of small quantities of 3,3 -diiodothyronine and of 3,3 5 -triiodothyroninc in thyroid tissue has been reported (Roche et al., 1956b), but this observation has not yet been confirmed. 

It has been known for some time that a difference between the physiological disposition of 3,5,3 -l-triiodothyronine and that of L-thyroxine probably accounts for the more rapid production of metabolic effects in vivo by the former compound (cf. Van Arsdel et al., 1954). More recently, it has become apparent that the lesser in vivo potency of certain compounds with altered side chains (the n-isomers as well as the acetic and propionic acid analogs of both thyroxine and triiodothyronine) probably results from a lower concentration of these analogs in the peripheral tissues (Larson and Albright, 1958 Tapley et al., 1959 Hatfield et at., 1960, 1961). As an example, the significance of the difference in the physiological disposition of the D- and L-isomers of thyroxine will be briefly considered. 

Three pathways for triiodothyronine degradation have been described oxidation, deiodination, and conjugation. The products of oxidation to acid have been found in the bile of rats after intraperitoneal administration of triiodothyronine. Triiodothyronine may be deiodinated to yield 3,3 -thyronine. This reaction may be of considerable physiological significance because the dehalogenation of Triac provides a means by which a very active compound can be converted to an inactive substance. Glucuronides and sulfates of triiodothyronine have been found in blood, and it is likely that they are synthesized in the liver. 

The chemical structure of the hormone that is active under physiological conditions is still under investigation. Although thyroxine administration undoubtedly corrects the metabolic and clinical alterations that occur after thyroidectomy, and although thyroxine acts on mitochondria in vitro, these observations constitute no proof that thyroxine is the compound that is active in normal physiological conditions. The belief that thyroxine is the active hormone was shattered when 3,5, 3 -triiodothyronine was isolated from blood and thyroid and when it was established that triiodothyronine is more potent than thyroxine on a molecular basis. The discovery of active compounds different from thyroxine has stimulated more research on the physiological effects of thyroxine analogs. 

After Gross, Pitt-Rivers, and Roche and his coworkers isolated 3,5,3 -triiodothyronine, it was demonstrated that the triiodothyronine is much more active than thyroxine itself. Since, in addition to dehalogenation, thyroxine can also be decarboxylated, deaminated, or conjugated, the physiological activities of the products of these metabolic alterations were also investigated. 

Triiodothyronine and thyroxine are the physiologically active hormones of the thyroid gland. Tyrosine is the starting material for their synthesis. Gries and co-workers [62] have chromatographed thyroid-active iodoamino acids on cellulose G layers and obtained good separations of DL-thyroxine, DL-truodothyroxine, DL-diiodothyronine, dl-monoiodothyronine, diiodotyrosine and monoiodotyrosine. 

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