Iodine deiodinases

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+. 

Amiodarone may induce thyrotoxicosis (2% to 3% of patients) or hypothyroidism. It interferes with type I 5 -deiodinase, leading to reduced conversion of T4 to T3, and iodide release from the drug may contribute to iodine excess. Amiodarone also causes a destructive thyroiditis with loss of thyroglobulin and thyroid hormones. 

In humans, the major pathway in the metabolism of the thyroid hormones consists of the removal of iodine or deiodination. Three deiodinase isoenzymes, encoded on three distinct genes, catalyze the reductive deiodination. All three enzymes contain the rare amino acid seleno-cysteine. The essential trace element selenium therefore plays an important role in thyroid hormone economy. 

Three types of iodothyronine deiodinase remove iodine atoms from thyroxine to form the active thyroid hormone triiodothyronine and also to inactivate the hormone by removing additional iodine531 541-546 (see also Chapter 25). In this case the - CH2- Se- may attach the iodine atom, removing it as I+ to form -CH2-Se-I. The process could be assisted by the phenolic -OH group if it were first tautomerized (Eq. 15-60). 

When five patients with type 2 amiodarone-induced hyperthyroidism were treated with a combination of an oral cholecystographic agent (sodium ipodate or sodium iopanoate, which are rich in iodine and potent inhibitors of 5 -deiodinase) plus a thionamide (propylthiouracil or methimazole) after amiodarone withdrawal, all improved substantially within a few days and became euthyroid or... 

The current concept of the catalytic mechanism of the type I iodothyronine deiodinase is presented in Fig. 3. The iodine is removed from the substrate in the form of the iodonium (I+) ion and transferred to an enzyme SH group (E-SH). The resultant enzyme SI (E-SI) intermediate represents an oxidized form of the deiodinase from which native enzyme is regenerated by reduction with cofactor. The latter reaction is inhibited by PTU which reacts with E-Sl under formation of a stable enzyme-PTU mixed disulfide. 

Synergistic interactions occur in other tissues and can have important biological and clinical consequences. For example, die interaction between selenium and iodine has been investigated.It is known that deiodinases are selenoproteins and that they remove iodine from T4 to produce the biologically active T3. Also the selenoprotein glutathione peroxidase is active in the thyroid in the destruction of excess hydrogen peroxide and is therefore important in thyroid hormone production. In certain areas of the world, combined selenium and iodine deficiency can occur and affect treatment provision of selenium maybe necessary to correct hypothyroidism, but also may precipitate its onset. 

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... 

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). 

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. 

D. lodinated Radiocontrast Media Certain iodinated radiocontrast media (eg, ipodate) effectively suppress the conversion of T to T3 via 5 -deiodinase in the liver, kidney, and other peripheral tissues (Figure 38-2). Inhibition of hormone release from the thyroid may also play a part. Ipodate has proved to be very useful in rapidly reducing T3 concentrations in thyrotoxicosis. 

Figure 15.6 Structure of iodinated hormones and their metabolism prooess. Thyroxin (T4) synthesized in the thyroid was deiodinated in the blood and tissues by 5-deiodinase to 3,5, 3 -triiodothyronine (rT3> and by 5 -deiodinase to 3,5,3 -triiodothyronine (Ts). vvhich is then further deiodinated by 5-deiodinase to diiodothyronine (T2)-...

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