Iodothyronine metabolism

B53. Burger, A. G., Engler, D., Buergi, U Weissel, M., and Steiger, G Ether link cleavage is the major pathway of iodothyronine metabolism in the phagocytosing human leukocyte and also occurs in vivo in the rat. J. Clin. Invest. 71,935-949 (1983). 

The initial step after cellular uptake of T4 is metabolic transformation to 3,5,3, -tri-iodothyronine (T3) (Fig. 52-8), which interacts with cytosolic and nuclear receptors, as well as with synaptosomal membrane binding sites of unknown function [25], Cytosolic receptors are proteins of 70 kDa that do not appear to undergo translocation to cell nuclei, nor do they appear to be nuclear proteins that have leaked out of cell nuclei during cell rupture nuclear receptors are proteins of 50 70 kDa that have both DNA-and hormone-binding domains [25,26,28],... 

The thyroid hormone thyroxine (tetraiodo-thyronine, T4) and its active form triiodothyronine (T3) are derived from the amino acid tyrosine. The iodine atoms at positions 3 and 5 of the two phenol rings are characteristic of them. Post-translational synthesis of thyroxine takes place in the thyroid gland from tyrosine residues of the protein thyro-globulin, from which it is proteolytically cleaved before being released, iodothyronines are the only organic molecules in the animal organism that contain iodine. They increase the basal metabolic rate, partly by regulating mitochondrial ATP synthesis, in addition, they promote embryonic development. 

Hypothyroidism developed within 2 weeks of rifampicin therapy in these patients and resolved when it was withdrawn. Rifampicin increases thyroxine clearance, possibly by enhancing hepatic thyroxine metabolism and the biliary excretion of iodothyronine conjugates. In healthy volunteers rifampicin reduces circulating thyroid hormone concentrations without affecting thyrotropin, suggesting that rifampicin directly reduces thyroid hormone concentrations. 

E.V. Ivleva (1989a) found that, during the winter, Black Sea horse-mackerel displayed increased thyroid activity. This is directly related to the intensity of energy metabolism. Other workers found enhanced growth of the follicular cells of the thyroid gland of brown trout and brook trout during periods of low temperature (Woodhead and Woodhead, 1965a,b Drury and Eales, 1968), and increased thyroxine levels in the blood plasma (Eales et al, 1982). On the other hand, Leatherland (1994) has demonstrated a close positive correlation between water temperature and the concentrations of both forms of thyroid hormone (thyroxine and tri-iodothyronine) in the plasma of brown bullhead. 

Recent investigations of the metabolism of iodothyronines in different tissues especially of the rat have led to the recognition of at least three different iodothyron-ine-deiodinating enzymes [5-8] (Table I). These deiodinases have in common that they are located in the membrane fractions of the tissues and that they are stimulated by sulfhydryl (SH) compounds, especially dithiols [5-8]. However, important differences exist between the specificities and catalytic mechanisms of these enzymes, their tissue distribution, sensitivity to PTU and other inhibitors, and regulation by thyroid hormone [5-8]. The characteristics of the different deiodinases will be discussed in more detail in Sections 2 and 3. 

The concept that plasma membrane transport plays a key role in the regulation of intracellular thyroid hormone levels is supported by studies with a monoclonal antibody against an antigen exposed on rat liver cells [107], This antibody inhibited the uptake of different iodothyronines by rat hepatocytes under initial rate conditions as well as the metabolism of these compounds during prolonged incubations [107]. Uptake and metabolism of T4, T3 and rT3 were affected to the same extent, suggesting that a single system operates in the transport of different iodothyronines, which is opposite to the view advanced above. However, it is not excluded that the antibody interacts with a component of the plasma membrane and thereby affects multiple transport systems. 

Approximately 80% of T4 disposal is accomplished by reductive deiodination to T3 and rT3. Further monodeiodination, producing a cascade of lesser iodothyronines, degrades one-third to one-half of the T3 and one-third of the rT3. Approximately 20% of radio-labeled T4 is excreted as thyronine (T0). Other metabolic pathways combine side-chain modification and/or O-sulfate or O-glucuronide formation with deiodination. Tri- and tetraiodothyroacetic acids, 25 and 26, are examples of products of side-chain modification. 

Selenium This metal is an essential trace element that functions as a component of enzymes involved in antioxidant protection and thyroid hormone metabolism. The existence of a number of selenoproteins has been demonstrated. In several intra- and extracellular glutathione peroxidases and iodothyronine... 

T3) within the protein backbone of the thyroglobuiin protein in the follicular lumen. Endocytosis followed by proteolytic cleavage of thyroglobuiin releases the iodothyronines into the circulation. A schematic outline of iodine metabolism, with emphasis on the formation and secretion of thyroid hormones, is shown in Figure 52-3. 

Q. Liu, A.S. Clanachan and G.D. Lopaschuk, Acute effects of tri-iodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat hearts, Am. J. Physiol. 275(3), E392-399 (1998). 

Two reactions account for the metabolic fate of about 80% of the T4 in plasma about 40% is converted to T3 via 5 -deiodination (activation), and another 40% of the T4 is converted to rT3 by 5 -deiodination (inactivation). These two reactions are catalyzed by three enzymes designated types I, II, and III iodothyronine deiodinases (Figure 33-5 and Table 33-2). Types I and II both catalyze the 5 -deiodination reaction but differ with respect to substrate specificity, tissue distribution, and regulation. Type III is a 5-deiodinase, which catalyzes the removal of iodine from position 5 of the inner ring. Type I is deiodinase selenocysteine-containing microsomal enzyme present in the liver, kidney, and thyroid, with specificity for... 

Selenium, as selenocysteine, is incorporated into glutathione peroxidase (antioxidant), iodothyronine deiodinase (thyroid hormone regulation), and selenoprotein P (vitamin C metabolism). Prematurity, acute illness, chronic GI losses, and long-term selenium-free parenteral nutrition are associated with low serum selenium concentrations and decreased glutathione peroxidase activity. " The... 

Endocrine Effects. Thyroid hormone metabolism is the result of a balance in iodine and selenium levels. Selenium is a component of the deiodinase enzymes, including the Type I and Type II iodothyronine 5 -deiodinases, which convert the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) (Kohrle 1994 St Germain and Galton 1997). Iodine deficiency can lead to hypothyroidism but if iodine deficiency is accompanied by selenium deficiency, thyroid gland destruction may also occur (Contempre et al. 1991a Hofbauer et al. 1997). Supplementation of individuals deficient in both iodine and selenium with selenium produces a further decrease in thyroid function, but if selenium supplementation is preceded by normalization of iodine levels, normal thyroid function is restored (Contempre et al. 1991a, 1992). 

As a component of glutathione peroxidase and the iodothyronine 5 -deiodinases, selenium is an essential micronutrient for humans. Its role in the deiodinase enzymes may be one reason that children require more selenium for growth than adults. Selenium is also a component of the enzyme thioredoxin reductase, which catalyses the NADPH-dependent reduction of the redox protein thioredoxin. Other selenium-containing proteins of unknown functions, including selenoprotein P found in the plasma, have also been identified. Excess selenium administered as selenite and selenate has been shown to be metabolized to methylated compounds and excreted. 

Little is known about the specific biochemical mechanism(s) by which selenium and selenium compounds exert their acute toxic effects. Long-term effects on the hair, skin, nails, liver, and nervous system are also well documented, and a general theory has been developed to explain the toxicity of exposure to excess selenium, as discussed below. Generally, water-soluble forms are more easily absorbed and are generally of greater acute toxicity. Mechanisms of absorption and distribution for dermal and pulmonary uptake are unknown and subject to speculation, but an active transport mechanism for selenomethionine absorption in the intestine has been described (Spencer and Blau 1962). The mechanisms by which selenium exerts positive effects as a component of glutathione peroxidase, thioredoxin reductase, and the iodothyronine 5 -deiodinases are better understood, but the roles of other selenium-containing proteins in mammalian metabolism have not been clarified. 

The metabolism of selenium is now fairly well understood. To become incorporated into selenium-specific proteins (e.g., glutathione peroxidase, thioredoxin reductase, iodothyronine 5 -deiodinase) through a cotranslational mechanism requires that selenium be in the form of selenide (Sunde 1990). All forms of selenium can be transformed to selenide, although the rates of transformation vary. For example, selenate is not converted to selenide as readily as selenite. The formation of selenide from selenocysteine requires a specific enzyme, selenocysteine (3-lyase, which catalyzes the decomposition of selenocysteine to alanine and hydrogen selenide. Excess selenium is methylated and exhaled or excreted in the urine in both humans and animals. Further research is required to determine which selenium metabolites or intermediates lead to toxicity. 

Behne S, Kyriakopoulos A, Gessner H, et al. 1992. Type I iodothyronine deiodinase activity after high selenium intake, and relations between selenium and iodine metabolism in rats. J Nutr 122 1542-1546. 

B14a. Becker, D. V., and Prudden, J. F., The metabolism of I-labelled thyroxine, tri-iodothyronine and di-iodotyrosine by an isolated perfused rabbit liver. Endocrinology 64, 136-148 (1959). 

The thyroid gland is the source of two fundamentally different types of hormones, iodothyronines and calcitonin. The iodothyronine hormones—thyroxine (U) and triiodothyronine (T )—are essential for normal growth and development and play an important role in energy metabolism. Calcitonin is discussed in Chapter 61. 

---