Deiodination of thyroxine

Triiodothyronine (3, 5,3-L-triiodothyronine, T3) is a thyroid hormone. It is producedby outer ring deiodination of thyroxine (T4) in peripheral tissues. The biologic activity of T3 is 3-8 times higher than that of T4. T3 is 99.7% protein-bound and is effective in its free non-protein-bound form. The half-life of triiodothyronine is about 19 h. The daily tur nover of T3 is 75%. Triiodothyronine acts via nuclear receptor binding with subsequent induction of protein synthesis. Effects of thyroid hormones are apparent in almost all organ systems. They include effects on the basal metabolic rate and the metabolisms of proteins, lipids and carbohydrates. 

Figure 16.13 Deiodination of thyroxine in peripheral tissues formation of T3 and reverse-Ts. Thyroxine is 3,5,3, 5 tetraiodo-thyroxine (T4) which is converted to 3,5,3 triiodothyronine (T3) in normal condition but is converted to 3,3, 5 triiodothyronine (reverse T3) during starvation. The prime ( ) indicates the carbon number to which the iodine is attached in the second ring.

In addition to its function in thiol/disulfide exchange, Grx-1 also serves as an alternative electron donor to ribonucleotide reductase (Fernandes and Holmgren 2004), participates in deiodination of thyroxine to triiodothyronine (Takagi et al. 1989), and acts as a dehydroascorbate reductase for regenerating ascorbic acid (Washburn and Wells 1989). However, despite the potential role of Grx in... 

It is not yet known whether deiodination of thyroxine and triiodothyronine is complete or partial, or what route the degradation of the deiodi-nated products takes. Mono- and diiodotyrosine are said not to leave the thyroid as such, but are deiodinated and the iodine reutilized (320, 720). However, in liver and kidney diiodotyrosine can be converted to the corresponding pyruvic and lactic acids (873), and triiodothyronine and thyroxine give the corresponding pyruvic acids (721a). 

Inhibition of peripheral deiodination of thyroxine to the active 3,3 ,5-triiodothyronine with thiouracU derivatives... 

The deiodination of thyroxine in peripheral tissues results in the formation of 3,3, 5-tri-iodothyronine (T3) or 3,3 5 -tri-iodothyronine (reverse T3). Unlike T3, which is more physiologically active than thyroxine itself, reverse T3 has no physiological activity. It is possible that the ratio of T3 to reverse T3 may vary in various physiological and pathological conditions. For example, reverse T3 is found in high concentrations in amniotic fluid. After birth, the serum reverse T3 level falls while the level of normal T3 increases. It is therefore possible that reverse T3 may be a marker of congenital hypothyroidism in fetuses. Specific radioimmunoassays are available for the determination of reverse T3. 

Manna D, Mugesh G (2012) Regioselective deiodination of thyroxine by iodothyronine deiodinase mimics an unusual mechanistic pathway involving cooperative chalcogen and... 

The functional form of thyroxine (T3) is generated by the deiodination of T4, and PCBs can influence the tissue levels of this form by disturbing metabolism, as well as by reducing the binding of T4. PCBs have been shown to inhibit the sulfation of thyroid hormones and the deiodination of T4 to T3. They can also induce the glucuronyl transferase that conjugates T4 (Brouwer et al. 1998). 

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+. 

PTU possesses special benefit it inhibits peripheral deiodination, thereby blocking the conversion of thyroxine to the active hormone tri-iodothyronine. PTU is rapidly absorbed from the gut, reaching peak blood levels within one hour, and is excreted in urine as the inactive glucuronide within 24 hours. In contrast methimazole which is absorbed at variable rates, is excreted slower (only 65-70% within 48 hours in urine). The short plasma half-life of... 

Amiodarone inhibits the peripheral and possibly in-trapituitary conversion of thyroxine (T4) to triiodothyronine (Tj) by inhibiting 5 -deiodination. The serum concentration of T4 is increased by a decrease in its clearance, and thyroid synthesis is increased by a reduced suppression of the pituitary thyrotropin T3. The concentration of T3 in the serum decreases, and reverse T3 appears in increased amounts. Despite these changes, most patients appear to be maintained in an euthyroid state. Manifestations of both hypothyroidism and hyperthyroidism have been reported. 

Endocrine uses Hyperthyroidism P-blockade reduces unpleasant symptoms of sympathetic overactivity there may also be an effect on metabolism of thyroxine (peripheral deiodination from T to Tj. A nonselective agent (propranolol) is preferred to counteract both the cardiac (Pj and p ) effects, and tremor (p ). 

Flett, P.A. and J.F. Leatherland. In vitro hepatic monodeiodination of L-thyroxine and the temporal effect of 17/3-estradiol on deiodination of rainbow trout (Salmo gairdneri Richardson). Fish Physiol. Biochem. 6 129-138, 1989. 

There are three plausible pathways for the biosynthesis of triiodothyronine. It could be formed from one molecule each of mono- and diiodotyrosine in the same way as thyroxine can be formed from two molecules of diiodotyrosine or it could be formed by incomplete iodination of preformed thryonine or diiodothyronine or it could be formed by deiodina-tion of thyroxine. Formation by deiodination is favored by English work-... 

Selenium is a component of all three members of the deiodinase enzyme family, the enzymes responsible for deiodination of the thyroid hormones (Kohrle 1994 St. Germain and Galton 1997). The deiodinases contain a selenocysteine at the active site, which is required for catalytic activity. There are three types of deiodinases and they differ in terms of tissue distribution, reaction kinetics, efficiency of substrate utilization, and sensitivity to inhibitors. The first to be recognized as a selenoprotein was type I iodothyronine 5 -deiodinase which converts the prohormone thyroxine (T4) to the active form, triiodothyronine (T3) and to date, studies of the effects of excess selenium have focused on this protein. Under normal circumstances the human thyroid produces only 20-30% of its hormone as T3 the remainder is T4 (a minute amount of reverse T3 (rT3) is also produced), which is largely converted to active T3 by type I deiodinase located within the liver, euthyroid pituitary, kidney, thyroid, and brain. Type I deiodinase is a membrane bound protein and, thus, its activity has not been directly measured in studies of humans supplemented with selenium. Human studies have instead measured serum levels of T3, rT3, T4, and TSH. 

Margarity, M., Valcana, T., and Timiras, P. S., Thyroxine deiodination, cytoplasmic distribution and nuclear binding of thyroxine and triiodothyronine in liver and brain of young and aged rats, Mech. Ageing Dev., 29, 181, 1985. 

The endogenous secretion is estimated at a daily rate of around 90 pg of thyroxine and 10 pg of 3,3 ,5-triiodothyronine. The liver and kidneys deiodinate thyroxine to 3,3 ,5-triiodothyronine, the hormone, which binds with higher affinity at the nuclear receptor. 

Further metabolism of the thyroid hormones takes place in the liver and kidneys by deamination, decarboxylation, sulfatation or conjugation, but especially by deiodination, whereby around 20% of the iodide, which is set free, is reused for the synthesis of thyroxine. The biological half-life of thyroxine is around 190 hours that of 3,3 ,5-triiodothyronine is 19 hours. About 15% of the thyroid hormones are excreted via the faeces, and only minor amounts into the urine. 

Roti, S.L. Fang, K. Green, C.H. Emerson, and L.E. Braverman, Human placenta is an active site of thyroxine and 3,3, 5-triiodothyronine tyrosyl ring deiodination. J. Clin. Endocrinol. Metab. 53 498 (1981). 

J.T. Hidal, and M.M. Kaplan, Characteristics of thyroxine 5 -deiodination by cultured human placenta cells. Regulation by iodothyronines. J. Clin. Invest. 76 947 (1985). 

The myxoedematous form of endemic cretinism, which is still prevalent in many parts of the world (CoNTEMPRE et al. 1991), is not only due to the lack of iodine, but also of selenium. The selenoprotein type 1 5 -deiodinase catalyses the deiodination of the prohormone L-thyroxine (3,3 ,5,5 -tetraiodo-L-thyronine, T4) to the biologically active form 3,3 ,5-triiodo-L-thyronine (L-T3). During fetal development the maternal organism contributes at least minimal amounts of thyroid hormone for the fetus. After birth, the baby then slowly reaches the condition of thyroid hormone deficiency, because contin-... 

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