3,5,3-Triiodothyronine pathways

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. 

The coupling reaction by which the aromatic group from one residue of mono- or diiodotyrosine is joined in ether linkage with a second residue is also catalyzed readily by peroxidases. One dehydroalanine residue is formed for each molecule of hormone released.108 A possible mechanism involves formation of an electron-deficient radical, which can undergo (3 elimination to produce a dehydroalanine residue and an aromatic radical. The latter could couple with a second radical to form triiodothyronine or thyroxine. However, as depicted in Eq. 25-6, the radical coupling may occur prior to chain cleavage. While P elimination (pathway... 

OH-PCBs can also influence thyroxine metabolism. Some of the OH-PCBs that are retained in blood were shown to strongly inhibit sulfation of thyroxine in vitro [204-206]. As sulfation is a major regulation pathway of thyroxine in the fetus, the OH-PCBs may negatively influence the development of the fetus, and in particular fetal brain development [44]. Diodinase mediation is another pathway for thyroxine metabolism e.g., to the active hormone triiodothyronine. Hydroxylated metabolites of CB-77 were shown to inhibit triiodothyronine formation in an in vitro assay using rat hepatic microsomes [207],... 

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-... 

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. 

Figure 31.3 Possible intervention sites of dioxin-like oompounds at the level of the thyroid gland and in other processes such as thyroid binding to their binding proteins and metabolization. Adapted from Pooar et al, (2006). Full bold line boxes indicate the most consistent effects of dioxin-like compounds, whereas dotted boxes indicate conflicting results in literature. Black intervention of dioxin-like compounds in specific pathways consistent effect through literature gray conflicting results in literature. TG, thyroglobulin T4, thyroxine T3, triiodothyronine TSH-R, thyroid-stimulating hormone receptor NIS, sodium iodide symporter TPO, thyroid peroxidase CatB, cathepsin B.

Figure 88.2 The possible pathway of maternal-fetal TH metabolism influenoed by excess iodine. Abbreviations T4, thyroxine T3, triiodothyronine T2, 3,3 -L-diiodothyronine rl3, reverse triiodothyronine D1, type 1 iodothyronine deiodinase D2, type 2 iodothyronine deiodinase D3, type 3 iodothyronine deiodinase.

Fig. 1. Schematic representation of the pathways of the biosynthesis of the thyroid hormones. The sites of biosynthetic defects are also indicated. [L] = active iodide," MIT = monoiodotyrosine, DIT = diiodotyrosine, Ts — triiodothyronine, T = thyroxine, TBP = thyroid hormone-binding proteins.

With regard to the biosynthesis of triiodothyronine, two pathways are possible (1) enzymic reduction of one iodine atom from thyroxine, and (2) the coupling of one molecule of monoiodotyrosine with one molecule of diiodotyrosine. These alternative pathways are shown in the following diagram ... 

Larsen, Qualitative and quantitative differences in the pathways of extrathyroidal triiodothyronine generation between euthyroid and hypothyroid rats, J. Clin. Invest., 73 898 (1984). 

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. 

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