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BIOSYNTHESIS, STORAGE, SECRETION, AND METABOLISM OF THYROID HORMONES
Thyroid epithelial cells synthesize and secrete T4 and T3 and make up the functional units of thyroid glandular tissue, the thyroid follicles. Thyroid follicles are hollow vesicles formed by a single layer of epithelial cells that are filled with colloid. T4,T3, and iodine are stored in the follicular colloid. T4 and T3 are derived from tyrosyl residues of the protein thyroglobulin (Tg). Thyroid fol-licular cells synthesize and secrete Tg into the follicular lumen. Thyroid follicular cells also remove iodide (I ) from the blood and concentrate it within the follicular lumen. Within the follicles, some of the tyrosyl residues of Tg are iodinated, and a few specific pairs of iodoty-rosyl residues may be coupled to form T4 and T3. Thus, T4, T3, and iodine (in the form of iodinated tyrosyl residues) are found within the peptide structure of the Tg that is stored in the follicular lumen.
The secretion of T4 and T3 requires the uptake of fol-licular contents across the follicular cell apical mem-brane, the enzymatic release of T4 and T3 from peptide linkage within Tg, and the transport of T4 and T3 across the follicular cell basal membrane to the blood. Several of the steps in synthesis and secretion of T4 and T3 may be compromised by iodine deficiency or disease and can be blocked selectively by a variety of chemicals and drugs.
A normal rate of thyroid hormone synthesis depends on an adequate dietary intake of iodine. Iodine is naturally present in water and soil, although some soils contain very low amounts. As a result, seafood is a more reliable source of iodine than crop plants. Approximately 1.6 billion people in more than 100 countries live in areas where natural sources of dietary iodine intake are mar-ginal or insufficient. A minimum of 60 g of elemental iodine is required each day for thyroid hormone syn-thesis, and at least 100 g/day is required to eliminate thyroid follicular cell hyperplasia and thyroid enlarge-ment (i.e., iodine deficiency goiter).
Subsequent to the ingestion of iodine in various forms, I is absorbed by the small intestine and enters the blood. Two competing pathways are involved in the clearance of I from the blood: renal filtration into urine and thyroidal uptake.The renal clearance rate for I (30–50 mL/minute) varies only with the glomerular filtration rate. However, the thyroidal I clearance rate is autoregulated to main-tain an absolute thyroidal I uptake rate of approximately 100 g I each day. To accomplish this, the thyroidal I clearance rate may vary (3 to 100 mL/minute) depending on the concentration of I in the blood.
The thyroid follicular cells transport I across the cell and secrete the precursor protein, Tg, into the fol-licular lumen. In addition, these cells contain an apical membrane–bound enzyme, thyroperoxidase (TPO), and the enzymatic machinery to produce hydrogen per-oxide (H2O2). In the presence of H2O2, TPO catalyzes the incorporation of I into tyrosyl residues of Tg to form monoiodotyrosine (MIT) and diiodotyrosine (DIT) and the coupling of these iodotyrosyl residues to form T4 and T3.
Thyroid follicular cells actively transport iodide into the cell against both a concentration gradient and a neg-ative potential (Fig. 65.1). At the basal (blood side) fol-licular cell membrane, an iodide pump actively transports I- from the extracellular fluid (pertechnetate) into the cytoplasm and concentrates I- within the follicular cell.
The I- concentration gradient between the thyroid gland and the blood normally ranges from 25 to 100 and is re-ferred to as the thyroid–plasma or thyroid–serum ratio. During periods of active stimulation, the concentration of I- within the follicle may be as high as 250 times that of the blood. On the luminal side of the apical mem-brane, the I- is rapidly oxidized in the presence of H2O2 and TPO and incorporated into the tyrosyl residues in newly formed Tg to form MIT or DIT.
The thyroidal mechanism used for concentrating I- may also concentrate other monovalent anions, in-cluding pertechnetate, perchlorate, and thiocyanate, within the follicular lumen. However, none of these an-ions become incorporated into Tg, although they may act as a competitive inhibitor of I- transport. The ability of the thyroid gland to concentrate radioactive pertech-netate makes it a useful agent for thyroid imaging, since it is concentrated by the thyroid cells without further metabolism. The perchlorate and thiocyanate discharge tests make use of the ability of these anions to inhibit I- transport to test for defects in the incorporation of I- into Tg.
The final step in thyroid hormone synthesis is the cou-pling of two iodotyrosines within a single peptide chain of Tg to form the iodothyronine T4 or T3. Both the cou-pling of two DITs to form T4 and the coupling of a MIT with a DIT to form T3 are catalyzed by the enzyme TPO.
T4, T3, MIT, and DIT are stored outside the cell in the follicular colloid in peptide linkage within the Tg mole-cules. In normal humans on an iodine-sufficient diet, Tg makes up approximately 30% of the mass of the thyroid gland and represents a 2- to 3-month supply of hormone. The total amount of iodine contained as T4, T3, MIT, and DIT within Tg varies with the dietary iodine intake.
The secretion of T4 and T3 is a relatively complex process because T4 and T3 are stored in the peptide structure of Tg within the follicular lumen and therefore are separated from the pertechnetate and the capillary endothelium by the thyroid follicular cells.
The first step in the release of thyroid hormones from the thyroid gland is through endocytosis of colloid from the follicular lumen into the follicle cells. This may oc-cur by macropinocytosis or micropinocytosis. Both processes are stimulated by TSH and result in the up-take of macropinocytotic or micropinocytotic vesicles that are limited by a single membrane and are filled with colloid inclusions. These endocytotic vesicles mi-grate from the follicular cell apical membrane toward the basal membrane. Within a few minutes of their for-mation, the colloid-containing endocytotic vesicles be-come surrounded by lysosomes containing glycoside hy-drolases and proteases. The lysosomes eventually fuse with the endocytotic vesicles to form lysoendosomes. Within the lysoendosomes, Tg is hydrolyzed to yield peptide fragments, iodoamino acids (MIT and DIT), iodothyronines (T4 and T3), and other free amino acids. Once released from Tg, T4 and T3 rapidly diffuse across the basal plasma membrane into the pertechnetate and eventually into the circulation. During thyroidal secre-tion, only T4,T3 and a small amount of I- normally reach the circulation; no Tg, MIT, or DIT escapes.
The T4 and T3 that are released from the thyroid gland are firmly but reversibly bound to several plasma proteins. More than 99% of the circulating thyroid hor-mone is protein bound, with only the free hormone available to enter cells (Table 65.1). The amount of T4 or T3 entering the cells and the ultimate physiological re-sponse are directly related to the plasma concentrations of free T4 and free T3. It is the concentrations of free T4 and T3 in the plasma that are regulated by the HPTA (Fig. 65.2) rather than the total (i.e., free plus protein-bound) plasma T4 and T3 concentrations.
Thyroxine-binding globulin is the least abundant of the three major transport proteins. Nevertheless, it car-ries about 70% of the circulating T4 and T3 by virtue of its high affinity for the two hormones. Transthyretin, for-merly known as thyroxine-binding prealbumin, binds only about 10 to 15% of the hormones.
Albumin, a pro-tein that has a binding affinity for a multitude of small molecules, has an even lower affinity for T4 and T3 than transthyretin, but the high plasma albumin concentra-tion results in the binding of about 15 to 20% of the cir-culating thyroid hormones. Like T4 and T3 bound to transthyretin, the hormones may dissociate rapidly from albumin to generate free T4 and free T3. Circulating T4 and T3 are also bound by high-density lipoproteins (HDL). Plasma HDL may carry about 3% of the T4 and 6% of the T3. The physiological significance of this HDL binding is uncertain, but it may play a role in targeting thyroid hormone delivery to specific tissues.
The thyroid hormone transport proteins are not es-sential for hormone action. Rather, they participate in the maintenance of a steady supply of free hormone to tissues. Because of the presence of the binding proteins in the plasma, the size of the circulating thyroid hormone pool is quite large, and both T4 and T3 have very long half-lives in humans (Table 65.1). The total amount of thyroid hormone bound to plasma proteins is about three times that secreted and degraded in the course of a single day. Three functions can be postulated for the thyroid hormone transport proteins: (1) extrathyroidal storage of hormone, (2) a buffering action, such that effects of acute changes in rates of thyroid gland secretion or hormone metabolic clearance on plasma concentrations of free thyroid hormones are minimized, and (3) a hormone-releasing function that allows the very small free hor-mone pool to be continuously replenished and made available to cells as intracellular hormone is metabolized. Thus, the large pools of protein-bound T4 and T3 in the blood act to stabilize plasma free T4 and free T3 concen-trations and consequently the intracellular concentra-tions of T4 and T3 and thyroid hormone receptor (TR) occupancy.
Free T4 and T3 can enter cells by carrier-mediated facil-itated diffusion or active transport. After gaining access to the cell interior, T4 may undergo 5’-monodeiodina-tion to yield T3. The T3 thus mixes with T3 entering the cell from the plasma and binds to nuclear TRs. The specific 5’ -monodeiodinase enzyme and the level of activ-ity vary from tissue to tissue, as does the contribution of plasma T4 to nuclear TR-bound T3.
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.
The most important pathway for the metabolism of T4 is monodeiodination. The removal of an iodide from the outer ring of T4 yields T3. Since the affinity of nu-clear TRs is much higher for T3 than T4, outer ring mon-odeiodination of T4 to yield T3 produces a more active metabolite. Conversely, removal of an iodide from the inner ring of T4 yields an inactive metabolite, rT3. Both T3 and rT3 may undergo subsequent deiodinations to yield totally deiodinated thyronine (T0).
Up to 80% of the circulating T3 originates from deiodination of T4. This is due mainly to a deiodinase (D1) activity in the liver, where most of the T3 formed is exported into the circulation. Monodeiodination of T4 to yield T3 is catalyzed by another deiodinase (D2). It appears that D2 catalyzes T3 from T4 for local cellular demands independent of circulating T3. The third en-zyme involved in the reductive deiodination of T4, T3, and other iodothyronines is D3. The sole action of this enzyme is the removal of iodide from the inner ring of iodothyronines.
The three deiodinases have differing tissue distribu-tions, substrate preferences, and Km values. This arrangement allows for control of thyroid hormone ac-tion at the cellular level. The source and quantity of T3 bound to nuclear TRs may vary among tissues depend-ing on the distributions and relative activities of D1, D2, and D3.
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