Exogenous free iodotyrosine inhibits iodide transport through the sequential intracellular events

1994 ◽  
Vol 130 (6) ◽  
pp. 601-607 ◽  
Author(s):  
Michiyo Nasu ◽  
Masahiro Sugawara
Keyword(s):  
Los Angeles ◽  
Thyroid Peroxidase ◽  
Thyroid Cell ◽  
Camp Production ◽  
Thyroid Follicle ◽  
Iodide Uptake ◽  
Iodide Transport ◽  
Camp Generation ◽  
Iodotyrosine Deiodinase ◽  
Hormone Formation

Nasu M, Sugawara M. Exogenous free iodotyrosine inhibits iodide transport through the sequential intracellular events. Eur J Endocrinol 1944;130:601–7. ISSN 0804–4643 We describe a new function of exogenous iodotyrosine as a regulator of iodide transport. Porcine thyroid follicles in culture were preincubated with 0–20 μmol/l monoiodotyrosine or diiodotyrosine (DIT) in the presence of bovine thyrotropin (TSH) for 24 h; these iodotyrosines inhibited iodide uptake in a dose–response manner. Extracellular [125I]DIT was actively transported to the thyroid follicle in the presence of TSH or (Bu)2cAMP. Inhibition of iodide uptake by iodotyrosine required preincubation with iodotyrosine in the presence of TSH; without TSH, iodotyrosine was ineffective. Follicles preincubated with DIT for 24 h inhibited TSH-mediated cAMP production, which is an important signal for iodide transport. Inhibition of iodide uptake and cAMP generation by iodotyrosine was negated characteristically by 3-nitro-l-tyrosine, an inhibitor of iodotyrosine deiodinase, or by methimazole, an inhibitor of thyroid peroxidase. Our findings suggest that iodotyrosine regulates iodide transport through the following sequential intracellular events: TSH-dependent iodotyrosine transport into the thyroid cell; deiodination of iodotyrosine and release in iodide; iodine organification by the peroxidase system; inhibition of cAMP generation by organified iodine; and inhibition of iodide transport. Thus, exogenous iodotyrosine can serve as an inhibitor of thyroid hormone formation only when TSH is present M Sugawara, Wadsworth VA Hospital (11 IM), Wilshire and Sawtelle Blvds, Los Angeles, CA 90073, USA

Examination of antithyroid effects of smoking products in cultured thyroid follicles: only thiocyanate is a potent antithyroid agent

1992 ◽  
Vol 127 (6) ◽  
pp. 520-525 ◽  
Author(s):  
Haruhisa Fukayama ◽  
Michiyo Nasu ◽  
Saburo Murakami ◽  
Masahiro Sugawara
Keyword(s):  
Thyroid Hormone ◽  
Sodium Pump ◽  
De Novo ◽  
Serum Levels ◽  
Potassium Thiocyanate ◽  
Camp Production ◽  
Iodide Uptake ◽  
Iodide Transport ◽  
Efflux Inhibition ◽  
Hormone Formation

We studied the antithyroid action of cigarette smoking products (nicotine, cotinine, and thiocyanate) in the physiological culture system of porcine thyroid follicles. Iodide uptake, iodine organification, de novo thyroid hormone formation, and iodide efflux were measured in the presence of 0–200 μmol/l nicotine, cotinine, or potassium thiocyanate. Nicotine and cotinine did not inhibit iodide transport or thyroid hormone formation. Thiocyanate concentrations equivalent to serum levels of smokers showed three independent antithyroid actions: (i) inhibition of iodide transport, (ii) inhibition of iodine organification, and (iii) increased iodide efflux. Inhibition of iodide transport by thiocyanate was competitive with iodide and independent of TSH concentration. Thiocyanate did not inhibit TSH mediated cAMP production or Na+K+ATPase activity, a sodium pump for iodide transport. When 50 μmol/l thiocyanate was added 2 h after incubation with iodide or when 1 μmol/l thiocyanate was added from the beginning of incubation, iodine organification was inhibited without changing iodide transport. De novo thyroid hormone formation was clearly inhibited by 50 μmol/l thiocyanate. Thiocyanate increased iodide efflux although the degrees of iodide efflux by 10 μmol/l and 100 μmol/l thiocyanate did not differ significantly. In summary, thiocyanate, a product of smoking, has three independent antithyroid activities. The data of iodide transport kinetics suggest that thiocyanate can be an antithyroid agent particularly in iodine deficiency.

Effect of exogenous hydrogen peroxide on iodide transport and iodine organification in FRTL-5 rat thyroid cells

1993 ◽  
Vol 129 (1) ◽  
pp. 89-96 ◽  
Author(s):  
Ge Chen ◽  
A Eugene Pekary ◽  
Masahiro Sugawara ◽  
Jerome M Hershman
Keyword(s):  
Hydrogen Peroxide ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Thyroid Peroxidase ◽  
Thyroid Cells ◽  
Iodide Transport ◽  
Biphasic Effect ◽  
Rat Thyroid ◽  
Camp Levels ◽  
Hormone Formation

Hydrogen peroxide plays an important role in the regulation of iodination and thyroid hormone formation. In the present study, the effect of exogenous H2O2 on 125I transport and organification was investigated in FRTL-5 rat thyroid cells. Less than 20 passages after subcloning, cells in 24-well plates (6 × 104 cells/well) were maintained in a thyrotropin (TSH)-containing medium (6H) for 3 days. A TSH-free medium (5H) was then used for the next 7 days. A 1-h exposure to H2O2 stimulated 125I transport and 125I organification at 0.1–0.5 mmol/l H2O2 and had a toxic effect on FRTL-5 cells at 5 mmol/l. Hydrogen peroxide (0.5 mmol/l) augmented the iodide transport and iodine organification induced by TSH (333U/l) by two- and threefold, respectively. The biphasic effect of H2O2 was blocked totally by 5–200 μg/l of catalase. Catalase by itself did not influence TSH-mediated 125I transport and 125I organification. Hydrogen peroxide (0.5 mmol/l) added to cells in 5H medium increased Na+K+-ATPase activity twofold. Ouabain (1 mmol/l), an inhibitor of Na+K +-ATPase, completely inhibited the twofold increase in 125I transport induced by 0.5 mmol/l H2O2 but only inhibited H2O2-induced 125I organification by 28%. Methimazole (1 mmol/l), an inhibitor of thyroid peroxidase, had no effect on H2O2-mediated 125I transport but totally blocked the fivefold rise in 125I organification induced by 0.5 mmol/1 H2O2. The effect of H2O2 on intracellular cyclic adenosine monophosphate (cAMP) levels also was studied. Hydrogen peroxide (0.5 mmol/l) decreased baseline and 160 mU/l TSH-induced cAMP levels by 35 and 87%, respectively, while a 3-h incubation with 0.5 mmol/l H2O2 increased Na + K +-ATPase in 5H and 6H media. We conclude that H2O2 plays an important role in the regulation of iodide transport and organification and also may affect signal transduction and the electrochemical gradient in thyroid cells. Our results also provide evidence that functional thyroid peroxidase activity is present in FRTL-5 cells.

Interaction of endothelin-1 with porcine thyroid cells in culture: a possible autocrine factor regulating iodine metabolism

1994 ◽  
Vol 142 (3) ◽  
pp. 463-470 ◽  
Author(s):  
T Tsushima ◽  
M Arai ◽  
O Isozaki ◽  
Y Nozoe ◽  
K Shizume ◽  
...  
Keyword(s):  
Binding Capacity ◽  
Specific Binding ◽  
Thyroid Cell ◽  
Scatchard Analysis ◽  
Camp Production ◽  
Iodide Uptake ◽  
Single Class ◽  
Thyroid Cells ◽  
Cells In Culture ◽  
Iodine Metabolism

Abstract Although endothelins were originally discovered as peptides with vasoconstrictor activity, recent studies have indicated a number of endothelin (ET)-induced hormonal functions in various tissues. We have studied the interaction of endothelins with porcine thyroid cells in culture. Specific binding of 125I-labelled ET-1 was demonstrated in porcine thyroid cells. The binding was displaced equally by unlabelled ET-1 and ET-2, but receptor affinity for ET-3 was lower than that for ET-1 and -2. Scatchard analysis of the data revealed a single class of high-affinity ET-1 receptors with a Kd of 0·45 nmol/l and a binding capacity of 2100 sites/cell. SDS-PAGE and autoradiography of 125I-labelled ET-1 cross-linked with thyroid cell membranes demonstrated ET-1 binding sites with an apparent molecular weight of 50 kDa. These results indicated that ET-1 receptors in thyroid cells are type A ET receptors. In association with the presence of ET-1 receptors, porcine thyroid cells responded to ET-1 and ET-2 with an increase in c-fos mRNA expression. Although ET-1 did not affect DNA synthesis stimulated by either EGF or IGF-I, it dose-dependently inhibited TSH-induced iodide uptake and also inhibited iodide uptake stimulated by forskolin and 8-bromo-cAMP. ET-1 had no effect on TSH-stimulated cAMP production. Thus, ET-1 inhibited TSH-induced iodine metabolism by acting at the steps distal to cAMP production. In agreement with a recent report, immunoreactive ET-1 was detected in medium conditioned by porcine thyroid cells. Antibody to ET-1 was found to increase TSH-induced iodide uptake. These results are compatible with the notion that ET-1 negatively regulates TSH-induced iodide uptake in an autocrine manner. Journal of Endocrinology (1994) 142, 463–470

Iodide autoregulation of functional and morphological differentiation events in the FRTL-5 rat thyroid cell strain

1990 ◽  
Vol 124 (1) ◽  
pp. 19-NP ◽  
Author(s):  
H. M. Beere ◽  
S. Tomlinson ◽  
S. P. Bidey
Keyword(s):  
Sodium Perchlorate ◽  
Morphological Differentiation ◽  
Cell Strain ◽  
Thyroid Cell ◽  
Intracellular Camp ◽  
Inhibitory Effects ◽  
Iodide Uptake ◽  
Camp Generation ◽  
Rat Thyroid

ABSTRACT The role of cyclic AMP (cAMP) attenuation in mediating the autoregulatory actions of iodide on thyroid cell iodide uptake and surface morphological responses to TSH was investigated in the rat thyroid cell strain FRTL-5. Preincubation of cells for 6 h with up to 1 mmol sodium iodide/1 led to a progressive reduction in both accumulation of cAMP and iodide uptake responses to TSH. Forskolin-mediated accumulation of cAMP and iodide uptake responses were similarly reduced after preincubation with iodide, whilst the iodide accumulation response to dibutyryl cAMP (dbcAMP) was unaffected. The inhibitory effects of iodide on TSH or forskolin-responsive iodide accumulation were not seen if preincubation was limited to 3 h, and were also abolished by the thionamide drug methimazole (1 mmol/l). Medium containing 1 μmol iodide/l prevented the appearance of the surface microvilli and pseudopodia normally observed after re-addition of TSH or forskolin, although cytoplasmic retraction was still apparent under such conditions. In contrast, iodide was without effect on the ability of dbcAMP (1 mmol/l) to induce cytoplasmic retraction and the formation of microvilli and pseudopodia. Inclusion of 1 mmol sodium perchlorate/l together with iodide during preincubation failed to prevent or reduce the suppression by iodide of either iodide uptake or surface morphological differentiation, suggesting that both aspects of autoregulation may involve surface actions of organified iodide. These observations indicate that in FRTL-5 cells, autoregulation by iodide of both the functional and surface morphological actions of TSH principally reflects the attenuating activities of organified iodide on intracellular cAMP generation. Journal of Endocrinology (1990) 124, 19–25

The inhibitory effect of iodide on growth of rat thyroid (FRTL-5) cells

1988 ◽  
Vol 119 (1) ◽  
pp. 145-151 ◽  
Author(s):  
Motoyasu Saji ◽  
Osamu Isozaki ◽  
Toshio Tsushima ◽  
Mariko Arai ◽  
Megumi Miyakawa ◽  
...  
Keyword(s):  
Cell Growth ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Camp Production ◽  
Iodide Uptake ◽  
Concentration Dependent Manner ◽  
Thyroid Cells ◽  
Camp Generation ◽  
Rat Thyroid ◽  
Sites Of Action

Abstract. The effect of iodide on growth of rat thyroid cells (FRTL-5) was studied. TSH-stimulated cell growth was inhibited by iodide in a concentration-dependent manner, and an effect of iodide was detected at 10−6 mol/l. KClO4 or 1-methylimidazole-2-thiol blocked the effect of iodide, suggesting that iodide uptake and its organification are required to produce the inhibitory effect of iodide on cell growth. Iodide not only decreased TSH-stimulated cAMP production in FRTL-5 cells but also cell growth induced by cAMP. These observations suggest that iodide inhibits TSH-stimulated growth of the cells by attenuating cAMP production and also by acting on the step(s) distal to cAMP generation. The inhibitory effect of iodide was also seen in growth stimulated by insulin, insulin-like growth factor-I or 12-O-tetradecanoyl phorbol 13-acetate, suggesting multiple sites of action of iodide in the process of growth of FRTL-5 cells.

Evidence for Competitive Inhibition of Iodide Uptake by Perchlorate and Translocation of Perchlorate into the Thyroid

2004 ◽  
Vol 23 (1) ◽  
pp. 17-23 ◽  
Author(s):  
Rebecca A. Clewell ◽  
Elaine A. Merrill ◽  
Latha Narayanan ◽  
Jeffery M. Gearhart ◽  
Peter J. Robinson
Keyword(s):  
Mode Of Action ◽  
Competitive Inhibition ◽  
Potential Effect ◽  
Quantitative Model ◽  
Published Data ◽  
Data Sets ◽  
Thyroid Follicle ◽  
Iodide Uptake ◽  
Iodide Transport ◽  
Pbpk Models

Various published data sets that investigate the potential effect of exogenous perchlorate ( [Formula: see text]) on the uptake of iodide in the thyroid and subsequent changes in thyroid hormone levels are available. In order to best use the data towards the prediction of human health effects resulting from [Formula: see text] exposure, the available literature data must be integrated into a self-consistent, coherent, and parsimonious quantitative model based on the most likely mode of action of perchlorate effect on thyroid function. We submit that the simplest mode of action for [Formula: see text] in the thyroid that remains consistent with all available data involves competitive inhibition of iodide transport into the thyroid follicle, transport of perchlorate into the thyroid follicle against a concentration gradient, further transport into the thyroid lumen (where it may again interfere with iodide transport), and, finally, passive diffusion back into the blood. We believe this description of perchlorate’s kinetic behavior should serve as the foundation for predictive physiologically based pharmacokinetic (PBPK) models and as a working hypothesis for further experimental exploration.

scholarly journals Differential effects of natural flavonoids on growth and iodide content in a human Na*/I- symporter-transfected follicular thyroid carcinoma cell line

2004 ◽  
pp. 557-564 ◽  
Author(s):  
JP Schroder-van der Elst ◽  
D van der Heide ◽  
JA Romijn ◽  
JW Smit
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Cell Line ◽  
Cancer Cell ◽  
Cancer Cell Line ◽  
Thyroid Peroxidase ◽  
Thyroid Cancer Cell ◽  
Iodide Uptake ◽  
Iodide Transport

OBJECTIVE: Natural flavonoids (plant pigments) have been shown to inhibit thyroid peroxidase (TPO) in vitro and the growth of thyroid cancer cell lines. We have studied the role of flavonoids on the iodide transport and the growth of the human follicular thyroid cancer cell line (FTC133) which was stably transfected with the human Na(+)/I(-) symporter (hNIS). DESIGN AND METHODS: Cells were treated with flavonoids (0.5-50 microM) for 0, 2, 4 and 6 days; (125)I content and (125)I efflux of the cells and DNA content were measured. RESULTS: Cell growth was inhibited significantly at day 6 by most flavonoids. Eight out of ten flavonoids decreased the (125)I content of the cells at day 4. Morin did not influence the (125)I content of the cells and, surprisingly, myricetin increased the (125)I content of the cells. Kaempferol, apigenin, luteolin and F21388 decreased NIS mRNA expression after 15, 29 and 48 h; after 96 h NIS mRNA returned to normal. CONCLUSION: As TPO is not present in this cell line, the effects of the flavonoids on the iodide uptake are not related to organification. Myricetin was the only flavonoid studied that increased the influx and decreased the efflux of iodide. The effect of myricetin (decreased growth and increased retention of iodide) can be of therapeutic value in the radioiodide treatment of thyroid carcinoma.

Dobutamine Antagonizes Epinephrine's Biochemical and Cardiotonic Effects 

1998 ◽  
Vol 89 (1) ◽  
pp. 49-57 ◽  
Author(s):  
Richard C. Prielipp ◽  
Drew A. MacGregor ◽  
Roger L. Royster ◽  
Neal D. Kon ◽  
Michael H. Hines ◽  
...  
Keyword(s):  
Artery Bypass ◽  
Phase 1 ◽  
Human Lymphocytes ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Camp Production ◽  
Isobolographic Analysis ◽  
Camp Generation ◽  
Vitro Model

Background Patients may receive more than one positive inotropic drug to improve myocardial function and cardiac output, with the assumption that the effects of two drugs are additive. The authors hypothesized that combinations of dobutamine and epinephrine would produce additive biochemical and hemodynamic effects. Methods The study was performed in two parts. Phase 1 used human lymphocytes in an in vitro model of cyclic adenosine monophosphate (cAMP) generation in response to dobutamine (10(-8) to 10(-4) M) or epinephrine (10(-9) M to 10(-5) M), and dobutamine and epinephrine together. Phase 2 was a clinical study in patients after aortocoronary artery bypass in which isobolographic analysis compared the cardiotonic effects of dobutamine (1.25, 2.5, or 5 microg x kg(-1) x min(-1)) or epinephrine (10, 20, or 40 ng x kg(-l) x min(-1)), alone or in combination. Results In phase 1, dobutamine increased cAMP production 41%, whereas epinephrine increased cAMP concentration approximately 200%. However, when epinephrine (10(-6) M) and dobutamine were combined, dobutamine reduced cAMP production at concentrations between 10(-6) to 10(-4) M (P = 0.001). In patients, 1.25 to 5 microg x kg(-1) x min(-1) dobutamine increased the cardiac index (CI) 15-28%. Epinephrine also increased the CI with each increase in dose. However, combining epinephrine with the two larger doses of dobutamine (2.5 and 5microg x kg(-1) x mi(-1)) did not increase the CI beyond that achieved with epinephrine and the lowest dose of dobutamine (1.25 microg x kg(-1) x min(-1)). In addition, the isobolographic analysis for equieffective concentrations of dobutamine and epinephrine suggests subadditive effects. Conclusions Dobutamine inhibits epinephrine-induced production of cAMP in human lymphocytes and appears to be subadditive by clinical and isobolographic analyses of the cardiotonic effects. These findings suggest that combinations of dobutamine and epinephrine may be less than additive.

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