Iodine distribution and turnover in humans can be visualized in Fig. 42.4. Hormone-associated iodine (HI) is found in stool (10 µg HI), urine (390 µg I), thyroid tissues (10 µg HI in the extracellular fluid, 60 µg HI, 80 µg I), and the diet (320 µg I, 20 µg I, 50 µg I in thyroglobulin). Thyroid peroxidase (TPO), an enzyme complex located in the apical membrane, catalyzes the sequence of reactions involved in the formation of thyroid hormones. Hydrogen peroxide (H2O2) serves as the immediate oxidant for this reaction, and its generation in the follicular lumen is facilitated by dual oxidases (DUOX1, DUOX2) present in the apical plasma membrane.

When iodide availability is limited, the formation of T3 is favored. This is because T3 is three times more potent than T4, resulting in a higher concentration of active hormone per molecule of organified iodide. Additionally, T3 proportionally increases when the thyroid gland is hyperstimulated by thyroid-stimulating hormone (TSH) or other activators.

The secretion of thyroid hormones occurs following the iodination of thyroglobulin, which is then stored as colloid in the follicular lumen. The release of T4 and T3 into the bloodstream is initiated through the endocytosis of colloid via macro- and micropinocytosis. Endocytotic vesicles fuse with lysosomes, leading to the degradation of thyroglobulin. This process also releases monoiodotyrosine (MIT) and diiodotyrosine (DIT) molecules. Within the follicular cell, MIT and DIT undergo rapid deiodination by iodotyrosine deiodinase, a specific enzyme that cannot utilize T4 and T3 as substrates. The iodide released from this deiodination process is then recycled for the synthesis of T4 and T3. Amino acids resulting from the digestion of thyroglobulin reenter the intrathyroidal amino acid pool and can be reused for protein synthesis. Normally, only minor amounts of intact thyroglobulin leave the follicular cell. Enzymatically released T4 and T3 are transported across the basal side of the cell and enter the bloodstream.

The synthesis and secretion of thyroid hormones by the thyroidepithelial cell are depicted in Fig. 42.5. The process involves the conversion of tyrosine to diiodotyrosine (DIT) or monoiodotyrosine (MIT), followed by their combination to form 3,5,3'-triiodothyronine (T3) or 3,5,3',5'-tetraiodothyronine (thyroxine, or T4). These reactions are further illustrated in Fig. 42.6, which shows the generation of iodide, MIT, DIT, T3, and T4.
•Fig. 42.4 Iodinedistributionandturnoverinhumans.HI,hormone-associatediodine.Stool 10 µg HIUrine 390 µg ITissues Thyroid Extracellular fluid 10 µg HI60 µg HI80 µg I400 µg IDiet 320 µg I20 µg I50 µg I thyroglobulin. This entire sequence of reactions is catalyzed by thyroid peroxidase (TPO), an enzyme complex that spans the apical membrane. The immediate oxidant (electron acceptor) for the reaction is hydrogen peroxide (H2O2). Generation of H2O2 in the follicular lumen is catalyzed by dual oxidases (DUOX1, DUOX2) that are also localized in the apical plasma membrane.
When iodide availability is restricted, formation of T3 is favored. Because T3 is three times as potent as T4, this response provides more active hormone per molecule of organified iodide. The proportion of T3 also increases when the thyroid gland is hyperstimulated by TSH or other activators.
Secretion of Thyroid Hormones
Once thyroglobulin has been iodinated, it is stored in the lumen of the follicle as colloid (see
Fig. 42.2 ). Release of T4 and T3 into the bloodstream is initiated by endocytosis of colloid from the follicular lumen by the processes of macroand micropinocytosis. Endocytotic vesicles then fuse with lysosomes and thyroglobulin is degraded (
Fig.
42.7
Fig. 42.5 ). MIT and DIT molecules, which also are released during proteolysis of thyroglobulin, are rapidly deiodinated within the follicular cell by the enzyme iodotyrosine deiodinase (see
Fig. 42.5 ). This deiodinase is specific for MIT and DIT and cannot use T4 and T3 as substrates. The iodide is then recycled into synthesis of T4 and T3. Amino acids from the digestion of thyroglobulin reenter the intrathyroidal amino acid pool and can be reused for protein synthesis. Only minor amounts of intact thyroglobulin leave the follicular cell under normal circumstances. Enzymatically released T4 and T3 are transported across the basal side of the cell and enter the blood.
•Fig. 42.5 Synthesisandsecretionofthyroidhormonesbythethyroidepithelialcell.
I I I I 3,5,3¢ 5¢ -Tetraiodothyronine (thyroxine, or T4) NH2 CH2CHCOOHHO O I I NH2 CH2CHCOOHHO O I NH2 CH2CHCOOHHO I NH2 CH2CHCOOH + I I DIT DIT NH2 CH2CHCOOH + I I NH2 CH2CHCOOHHO I Diiodotyrosine (DIT) or NH2 CH2CHCOOHHO Monoiodotyrosine (MIT) NH2 CH2CHCOOHHO Tyrosine NH2 CH2CHCOOHI2 + HO
DIT MIT 3,5,3¢ -Triiodothyronine (T3) •Fig. 42.6 Reactionsinvolvedinthegenerationofiodide,MIT,DIT,T3,andT4.