Update on Intrathyroidal Iodine Metabolism

Abstract

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.

Exposure to DE-71 alters thyroid hormone levels and gene transcription in the hypothalamic–pituitary–thyroid axis of zebrafish larvae

“…The TPO enzyme, which is highly conserved among vertebrates, catalyzes the iodination of tyrosyl-residues in TG and their subsequent coupling to iodothyronines (Dunn and Dunn, 2001). The findings of our study showed that after exposure to DE-17, the transcription of TPO gene showed a trend toward but not a significant increase in the transcription of the TPO gene.…”

Waterborne exposure to PFOS causes disruption of the hypothalamus–pituitary–thyroid axis in zebrafish larvae

“…TPO catalyzes the iodination of tyrosyl residues in TG and their coupling into iodothyronines (Dunn and Dunn, 2001). In the present study, TPO gene expression remained unchanged while a down-regulation of TG gene expression was observed.…”

Perchlorate and ethylenethiourea induce different histological and molecular alterations in a non-mammalian vertebrate model of thyroid goitrogenesis

“…The up-regulation of RNA translation factors indicates that one arm of the TSH-induced cellular response in the amphibian thyroid aims at augmenting global translation rates. The upregulation of various genes implicated in ER function and vesicular protein transport is likely related to another major hallmark of TSH action, namely the stimulation of synthesis and secretion of TG, the main secretory product of thyroid follicular cells (Dunn and Dunn, 2001). The expression signature detected for transcripts related to ER function (hspa5, pdia6, ero1l, xbp1, edem1) is consistent with the critical role played by the ER for TG folding and M a n u s c r i p t 14 maturation (Arvan et al, 1997;Baryshev et al, 2004;Sargsyan et al, 2004).…”

“…In response to TSH stimulation, the thyroid tissue of all vertebrates produces and releases the same thyroid hormones (TH), thyroxine (T 4 ) and 3,5,3'-triiodothyronine (T 3 ), which play important roles for development, growth and metabolism (Leatherland, 1982;McNabb, 2007;Shi, 1999;Yen, 2001). Biosynthesis of TH is a multi-step process comprising iodide uptake by the sodiumiodide symporter (NIS), biosynthesis of thyroglobulin (TG), iodide organification by thyroid peroxidase (TPO) to yield iodothyronine-containing TG and finally, endocytosis and hydrolysis of iodinated TG to liberate TH (Dunn and Dunn, 2001). A hallmark of TSH action on thyroid follicular cells is to up-regulate the expression of many genes involved in TH synthesis and release (De Felice et al, 2004).…”