The resurgence of the clinical use of perchlorate as a means of controlling amiodarone-induced thyroid dysfunction has suggested a need for a more careful examination of the actions of this antithyroid anion. To accomplish this, it is essential to understand the chemical, biochemical, and

Perchlorate and the Thyroid Gland

The Na(+)/I(-) symporter (NIS) is the plasma membrane glycoprotein that mediates active I(-) transport in the thyroid and other tissues, such as salivary glands, stomach, lactating breast, and small intestine. In the thyroid, NIS-mediated I(-) uptake plays a key role as the first step in the biosynthesis of the thyroid hormones, of which iodine is an essential constituent. These hormones are crucial for the development of the central nervous system and the lungs in the fetus and the newborn and for intermediary metabolism at all ages. Since the cloning of NIS in 1996, NIS research has become a major field of inquiry, with considerable impact on many basic and translational areas. In this article, we review the most recent findings on NIS, I(-) homeostasis, and related topics and place them in historical context. Among many other issues, we discuss the current outlook on iodide deficiency disorders, the present stage of understanding of the structure/function properties of NIS, information gleaned from the characterization of I(-) transport deficiency-causing NIS mutations, insights derived from the newly reported crystal structures of prokaryotic transporters and 3-dimensional homology modeling, and the novel discovery that NIS transports different substrates with different stoichiometries. A review of NIS regulatory mechanisms is provided, including a newly discovered one involving a K(+) channel that is required for NIS function in the thyroid. We also cover current and potential clinical applications of NIS, such as its central role in the treatment of thyroid cancer, its promising use as a reporter gene in imaging and diagnostic procedures, and the latest studies on NIS gene transfer aimed at extending radioiodide treatment to extrathyroidal cancers, including those involving specially engineered NIS molecules.

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The Na+/I- symporter (NIS): mechanism and medical impact.

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.

Update on intrathyroidal iodine metabolism.

Thyroid toxicity of iodide excess has been demonstrated in animals fed with an iodide-rich diet; in vitro iodide is cytotoxic, inhibits cell growth, and induces morphological changes in thyroid cells of some species. In this study, we investigated the effect of iodide excess in an immortalized thyroid cell line (TAD-2) in primary cultures of human thyroid cells and in cells of nonthyroid origin. Iodide displayed a dose-dependent cytotoxicity in both TAD-2 and primary thyroid cells, although at different concentrations, whereas it had no effect on cells of nonthyroid origin. Thyroid cells treated with iodide excess underwent apoptosis, as evidenced by morphological changes, plasma membrane phosphatidylserine exposure, and DNA fragmentation. Apoptosis was unaffected by protein synthesis inhibition, whereas inhibition of peroxidase enzymatic activity by propylthiouracil completely blocked iodide cytotoxicity. During KI treatment, reactive oxygen species were produced, and lipid peroxide levels increased mark...

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Antonio Pereira

Papers

Identification of a major iodolipid from the horse thyroid gland as 2-iodohexadecanal.