Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.

LoPresti, Jonathan S.; Eigen, A; Kaptein, Elaine M.; Anderson, Kenneth P.; Spencer, Carole A.; Nicoloff, John T.

doi:10.1172/jci114343

Cited by 77 publications

(31 citation statements)

References 46 publications

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“…Surprisingly, we also found that the ‫ف‬ 7.5 kb mRNA encoding D2 was expressed in human cardiac and skeletal muscle in addition to cerebral cortex and placenta (12). The D2 activity in human skeletal muscle was comparable to that in BAT from chronically cold exposed rats (13), suggesting it contributes to the PTU-insensitive plasma T3 production in humans (14).…”

Section: Introductionmentioning

confidence: 63%

Type 2 iodothyronine deiodinase is highly expressed in human thyroid.

Salvatore¹,

Tu²,

Harney³

et al. 1996

J. Clin. Invest.

183

104

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Type 2 iodothyronine deiodinase (D2) is a recently cloned selenodeiodinase thought to provide intracellular 3,5,3 Ј triiodothyronine (T3) to a restricted group of tissues. We report here the presence of D2 mRNA in human thyroid at levels 50-150-fold higher than in placenta. Surprisingly, while type 1 deiodinase (D1) is known to be present in human thyroid, D2 has not been evaluated previously. D2 mRNA was especially high in thyroids from Graves' patients and in follicular adenomas. Stimulated thyroids had higher D2 to D1 mRNA ratios than normal or multinodular glands suggesting differential regulation of D1 and D2 expression. Microsomes from normal, Graves', and TSH-stimulated thyroids contained low K m D2 activity resistant to propylthiouracil (1 mM) or to inactivation by N -bromoacetyl T3, agents which block or inactivate D1. At 2 nM thyroxine (T4), 100 times the physiological-free T4 levels, 60-80% of T4 to T3 conversion in stimulated, but only 27% of that in normal thyroids, is catalyzed by D2. We conclude that intrathyroidal T4 to T3 conversion by D2 may contribute significantly to the relative increase in thyroidal T3 production in patients with Graves' disease, toxic adenomas, and, perhaps, iodine deficiency. ( J. Clin. Invest. 1996. 98:962-968.)

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Section: Introductionmentioning

confidence: 63%

Type 2 iodothyronine deiodinase is highly expressed in human thyroid.

Salvatore¹,

Tu²,

Harney³

et al. 1996

J. Clin. Invest.

183

104

View full text Add to dashboard Cite

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“…On the basis of these observations and on the fact that propylthiouracil, an inhibitor of D1 but not of D2, can only partially inhibit T 4 -to-T 3 conversion in T 4 -replaced hypothyroid subjects (8,16,29), it is believed that D2 is not only involved in the regulation of local thyroid hormone bioactivity but that it also contributes to circulating iodothyronine levels (2). Plasma iodothyronine levels depend not only on the iodothyronine-metabolizing enzymes but also, among other things, on thyroid function and plasma iodothyronine binding capacity.…”

Section: Discussionmentioning

confidence: 98%

A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

Peeters

Beld

Attalki

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

101

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Type II deiodinase (D2) is important in the regulation of local thyroid hormone bioactivity in certain tissues. D2 in skeletal muscle may also play a role in serum triiodothyronine (T 3) production. In this study, we identified a polymorphism in the 5Ј-UTR of the D2 gene (D2-ORFa-Gly3Asp). We investigated the association of D2-ORFa-Gly3Asp, and of the previously identified D2-Thr92Ala polymorphism, with serum iodothyronine levels. D2-ORFa-Gly3Asp was identified by sequencing the 5Ј-UTR of 15 randomly selected individuals. Genotypes for D2-ORFa-Gly3Asp were determined in 156 healthy blood donors (age 46.3 Ϯ 12.2 yr) and 349 ambulant elderly men (age 77.7 Ϯ 3.5 yr) and related to serum iodothyronine and TSH levels. D2-ORFa-Asp 3 had an allele frequency of 33.9% in blood bank donors and was associated with serum thyroxine (T 4; Gly/Gly vs. Gly/Asp vs. Asp/Asp ϭ 7.06 Ϯ 0.14 vs. 6.74 Ϯ 0.15 vs. 6.29 Ϯ 0.27 g/dl, P ϭ 0.01), free T 4 (1.22 Ϯ 0.02 vs. 1.16 Ϯ 0.02 vs. 1.06 Ϯ 0.04 ng/dl, P ϭ 0.001), reverse T 3 (P ϭ 0.01), and T3/T4 ratio (P ϭ 0.002) in a dose-dependent manner, but not with serum T 3 (P ϭ 0.59). In elderly men, D2-ORFa-Asp 3 had a similar frequency but was not associated with serum iodothyronine levels. This new polymorphism in the 5Ј-UTR of D2 is associated with iodothyronine levels in blood donors but not in elderly men. We hypothesize that this might be explained by the decline in skeletal muscle size during aging, resulting in a relative decrease in the contribution of D2 to serum T 3 production.iodothyronines; open reading frame; population; association THYROID HORMONE IS ESSENTIAL for growth, development, and regulation of energy metabolism (14). It stimulates metabolic rate by increasing ATP turnover and by regulating the expression of uncoupling proteins in the mitochondria of fat and skeletal muscle (26,33). Production of thyroid hormone is regulated by the classic hypothalamus-pituitary-thyroid axis, whereas the biological activity of thyroid hormone, i.e., the availability of triiodothyronine (T 3 ), is mainly regulated by the three different selenodeiodinases (D1-D3) (2, 15). Tissue distribution and enzymatic activity of the three deiodinases are highly specific, and they all play a different physiological role. D2 is present in brain, pituitary, thyroid, brown adipose tissue, skeletal muscle, and aortic smooth muscle cells in humans (2,6,15,17,20,30,31). It converts thyroxine (T 4 ) to T 3 by outer-ring deiodination, and it is important in the regulation of local thyroid hormone bioactivity in D2-expressing tissues. D2 in skeletal muscle may also contribute to serum T 3 production (2, 30).The mRNA of the D2 gene is unusually long (6 -7 kb) compared with the other two selenodeiodinases, containing long 5Ј-and 3Ј-untranslated regions (UTRs) (1, 3-5). The 5Ј-UTR of the D2 mRNA is ϳ700 nt long and has an inhibitory effect on D2 translation. It causes a fivefold reduction in D2 activity in HEK-293 cells (9). This 5Ј-UTR contains three short open reading frames [sORFs (1, 4, 5); Fig. 1]. The most ...

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“…However, the expression of DII in these tissues, as suggested by the results of the Northern analysis, could be of considerable physiologic importance. For example, LoPresti et al (61) have demonstrated that the serum T 3 level in euthyroid subjects is unaltered after 4 d by the administration of high doses of PTU, suggesting an important role for the DII in maintaining circulating T 3 concentrations in healthy humans. DII expression in skeletal muscle could provide a source for such T 3 production.…”

Section: Discussionmentioning

confidence: 99%

Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues.

Croteau¹,

Davey²,

Galton³

et al. 1996

J. Clin. Invest.

360

246

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The deiodination of thyroid hormones in extrathyroidal tissues plays an important role in modulating thyroid hormone action. The type II deiodinase (DII) converts thyroxine to the active hormone 3,5,3 Ј -triiodothyronine, and in the rat is expressed in the brain, pituitary gland, and brown adipose tissue (BAT). Complementary DNAs (cDNAs) for the types I and III deiodinases (DI and DIII, respectively) have been isolated and shown to code for selenoproteins. However, information concerning the structure of the mammalian DII remains limited, and the pattern of its expression in human tissues is undefined. We report herein the identification and characterization of rat and human DII cDNAs. Both code for selenoproteins and exhibit limited regions of homology with the DI and DIII. In the rat pituitary and BAT, DII mRNA levels are altered more than 10-fold by changes in the thyroid hormone status of the animal. Northern analysis of RNA derived from human tissues reveals expression of DII transcripts in heart, skeletal muscle, placenta, fetal brain, and several regions of the adult brain. These studies demonstrate that: ( a ) the rat and human DII are selenoproteins, ( b ) DII expression in the rat is regulated, at least in part, at the pretranslational level in some tissues, and ( c ) DII is likely to be of considerable physiologic importance in thyroid hormone economy in the human fetus and adult. ( J. Clin. Invest. 1996. 98:405-417.)

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Alterations in 3,3'5'-triiodothyronine metabolism in response to propylthiouracil, dexamethasone, and thyroxine administration in man.

Cited by 77 publications

References 46 publications

Type 2 iodothyronine deiodinase is highly expressed in human thyroid.

Type 2 iodothyronine deiodinase is highly expressed in human thyroid.

A new polymorphism in the type II deiodinase gene is associated with circulating thyroid hormone parameters

Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues.

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