Update on intrathyroidal iodine metabolism.

The thyroid concentrates iodide from the serum and oxidizes it at the apical membrane, attaching it to tyrosyl residues within thyroglobulin (Tg) to make diiodotyrosine and monoiodotyrosine. Major players in this process are Tg, thyroperoxidase (TPO), hydrogen peroxide, pendrin, and nicotinamide adenine dinucleotide phosphate (NADPH). Further action of TPO, hydrogen peroxide (H2O2), and iodinated Tg produce thyroxine (T4) and triiodothyronine (T3). Hormone-containing Tg is stored in the follicular lumen, then processed, most commonly by micropinocytosis. The lysosomal enzymes cathepsins B, L, and D are active in Tg proteolysis. Tg digestion leaves T4 and T3 intact, to be released from the cell, while the 3,5'-diiodotyrosine (DIT) and 3-iodotyrosine (MIT) are retained and deiodinated for recycling within the thyroid. Some areas of especially active recent research include: (1) the role of molecular chaperones in directing properly folded TPO and Tg to the apical membrane; (2) details of proteolytic pathways; (3) modulation of iodine metabolism, not only by thyrotropin (TSH) but by iodine supply and by feedback effects of Tg, glutathione, and inhibitory elements in the N-terminal region of Tg; and (4) details of Tg structure and iodotyrosyl coupling. Despite general agreement on the major steps in intrathyroidal iodine metabolism, new details of mechanisms are constantly being uncovered and are greatly improving understanding of the overall process.