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PubMed2001

Transfer of the human NaI symporter gene enhances iodide uptake in hepatoma cells.

UNLABELLED: The characteristic feature of thyroid cells of taking up iodide enables benign thyroid diseases and differentiated thyroid carcinoma to be successfully treated with radioiodide therapy. The transport of iodide across the cell membrane is mediated by the human NaI symporter (hNIS). We therefore investigated whether the accumulation of iodide may be induced by the retroviral transfer of the hNIS gene in nonthyroid tumor cells. METHODS: With use of a bicistronic retroviral vector for the transfer of the hNIS coding sequence and the hygromycin resistance gene, rat Morris hepatoma (MH3924A) cells were infected with retroviral particles and 32 hNIS-expressing cell lines were generated by hygromycin selection. After incubation of the genetically modified and wild-type hepatoma cells and the rat thyroid cell line FRTL5 with Na125I, the uptake and efflux of iodide were determined. In addition, the iodide distribution in rats bearing wild-type and genetically modified hepatomas was monitored. RESULTS: Genetically modified MH3924A cell lines accumulated up to 235 times more iodide than did noninfected hepatoma cells. The maximal iodide uptake in the cells was observed after 60 min incubation time. Competition experiments in the presence of sodium perchlorate revealed a dose-dependent decrease of iodide uptake (87%-92%). Moreover, carbonyl cyanide p-trifluoromethoxyphenylhydrazone led to a loss of accumulated I- (32%), whereas 4,4'-diisothiocyano-2,2'-disulfonic acid stilbene increased the I- uptake into the cells (22%). However, a rapid efflux of the radioactivity (80%) was observed during the first 10 min after 125I(-)-containing medium had been replaced by nonradioactive medium. In rats, the hNIS-expressing tumors accumulated six times more iodide than did the contralateral wild-type tumor as monitored by scintigraphy. The ex vivo quantitation of the iodide content performed 1 h after tracer administration in 1 g of tumor tissue revealed a 17-fold higher iodide accumulation in the genetically modified tumors. In accordance with the in vitro data, we also observed a rapid efflux of radioactivity from the tumor in vivo. CONCLUSION: The transduction of the hNIS gene per se is sufficient to induce 125I transport in Morris hepatoma cells in vitro and in vivo. With regard to a therapeutic application, however, additional conditions need to be defined that inhibit the iodide efflux from the tumor cells.

Animals↗
PubMed1993

Iodide modulation of the EDTA-induced iodine reductase activity of horseradish peroxidase by interaction at or near the EDTA-binding site.

Horseradish peroxidase (HRP) catalyses the reduction of iodinium ion (I+) to iodide by H2O2 in the presence of EDTA. I+ reduction occurs optimally at pH 6 whereas the enzyme catalyses iodide oxidation optimally at pH 3.5. Thus the two activities reside on the same enzyme with two characteristic pH optima. Iodide modulates the expression of the reductase activity by EDTA. Higher concentrations of iodide inhibit the reductase activity by EDTA. Nitrite, an electron donor, acts similarly to iodide. Both EDTA and nitrite competitively inhibit iodide oxidation, indicating that they compete with iodide for the same binding site for electron flow to the haem iron group. However, unlike iodide, EDTA converts compound I, not into the native enzyme, but into a compound absorbing at 416 nm which reduces I+ and then returns to the native form. The apparent equilibrium dissociation constant, KD, for the formation of the EDTA-HRP complex (15 mM) is doubled in the presence of iodide, indicating interference with EDTA binding by iodide. EDTA binds away from the haem iron centre and not through intramolecular Ca2+. The pH-dependence of EDTA binding indicates that an ionizable group of the enzyme with pKa 5.8, presumably a distal histidine, controls the binding. The data suggest that iodide competes with EDTA for compound I and modulates the iodine reductase activity by limiting the formation of the 416 nm-absorbing active compound.

Anions↗
PubMed1998

Regulation and tissue distribution of the human sodium iodide symporter gene.

OBJECTIVE: Iodide uptake by the thyroid gland is mediated by the sodium iodide symporter (NIS). In the present report, we have analysed the factors that modulate human NIS mRNA expression and iodide uptake in primary thyroid follicular cell (TFC) cultures. In addition, NIS mRNA tissue distribution was investigated. METHODS: Primary thyroid follicular cell cultures were treated with human recombinant TSH with or without cytokines for 72 h. Subsequently, NIS gene expression and iodide uptake were analysed using reverse transcription-polymerase chain reaction (RT-PCR) and 125I uptake, respectively. Human tissue samples were investigated for NIS gene expression using both RT-PCR and Northern blotting. RESULTS: Human TSH increased both NIS gene expression and iodide uptake in TFC cultures in a dose-dependent manner. Using concentrations of 0.1 U/l of hTSH, a minor increase in NIS gene expression was detected without a detectable increase in iodide uptake. IL-1 alpha, TNF alpha and IFN gamma at concentrations of 10(5) U/l all inhibited TSH-induced NIS gene expression and iodide uptake. In these experiments, there was a good correlation between NIS mRNA expression and iodide uptake. Using RT-PCR higher levels of NIS mRNA were detected in Graves' disease (GD) compared to multi-nodular goitre tissue samples. Stomach and salivary gland tissue also expressed NIS mRNA, whereas low levels were found in the mammary gland and extraocular muscle tissue. No expression was detected in the ovary, oesophagus, colon, extraocular fat or skin. In contrast, Northern blot analysis failed to detect NIS in stomach, salivary gland, intestinal fat or non-toxic multi-nodular goitre tissue samples, although this was present in GD thyroid tissue. CONCLUSION: TSH upregulates sodium iodide symporter gene expression and iodide uptake in primary thyroid follicular cell cultures, and this induction is modulated by cytokines. Variable levels of sodium iodide symporter mRNA are present in different tissue samples, with high expression evident in Graves' disease thyroid tissue.

Actins↗
PubMed1985

Further characterization of the iodide inhibitory effect on the cyclic AMP system in dog thyroid slices.

Iodide inhibits cyclic AMP accumulation in the thyroid by a process which is prevented by inhibition of iodide uptake and of thyroid peroxidase. By a similar process, it also exerts other independent effects such as the enhancement of iodinated protein release. Iodide inhibited the stimulation of adenylate cyclase by prostaglandin E1, cholera toxin and forskolin. The action of iodide was not relieved by phosphodiesterase inhibitors and was not additive with the effect of norepinephrine or adenosine. Iodide did not decrease the cellular level of ATP. The data are compatible with an inhibition of adenylate cyclase beyond the level of the receptor, presumably at the level of the catalytic unit or its interaction with the positive transducing unit NS. The effect of iodide required TSH for its expression but not for its installation. It was decreased under all conditions in which iodide organification was decreased: decreased iodide or increased methimazole concentration, absence of calcium in the medium, etc. However, the relation between iodide binding to proteins and effect was not linear. The effect was not relieved by washing in the absence of iodide and in the presence of perchlorate, but it was partly reversible in the presence of methimazole propylthiouracyl or thiourea. It was not relieved by cooling to 20 degrees C and cytochalasin b, which block stimulated thyroglobulin hydrolysis and iodothyronine release, nor by actinomycin D, cycloheximide, puromycin, mepacrine or indomethacin. The data suggest that iodide binds to a saturable cell component by a reaction which is reversible only in the presence of thiol-containing drugs.

1-Methyl-3-isobutylxanthine↗
PubMed1988

The role of the primitive sea in the natural selection of iodides as a regulating factor in inflammation.

Iodides have many non-endocrine biologic effects, including a role they play in the physiology of the inflammatory response. Iodides when given systemically or applied locally increase the movement of granulocytes into areas of inflammation. They improve the phagocytosis of bacteria by granulocytes and the ability of granulocytes to kill bacteria. They alter native protein to make it more susceptible to enzymes produced by granulocytes. They increase glandular secretions and make mast cells more labile. They concentrate around tumors and granulomas in man and animals. They also move into areas of tissue injury. When iodide is redistributing around sites of tumors or injuries there is decreased thyroid uptake and decreased renal excretion. The multiple effects of iodides have suggested that iodide may have a physiological role in inflammation. Iodides were once used widely in medicine, especially before a cure for syphilis. Understanding the many known effects of iodides requires crossing multiple fields. The purpose of this paper is to propose that the rising iodide content of the primitive sea played a role in the natural selection of a system which helped the organism recover from tissue injury or invasion. As primative life forms underwent mutations those with a defense system more responsive to environmental factors, such as iodide, had the best chance of survival. It was important for a defense system to move to any point of surface injury. The diverse biologic effects of iodides suggest a very primative role. This effect was so important that it was later internalized so that today iodides are concentrated in the host around sites of injury or tumor growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Determination of iodide with 1,3-dibromo-5,5-dimethylhydantoin (DBH) in comparison with the ICl-method. Analytical methods of pharmacopeias with DBH in respect to environmental and economical concern. Part 3.

USP 1995 (The United States Pharmacopeia, 23rd Edit., (1995), potassium iodide p. 1265, sodium iodide p. 1424), PH. EUR. 1997 (European Pharmacopoeia, third ed., Council of Europe, Strasbourg, (1997), potassium iodide p. 1367, sodium iodide p. 1493) and JAP 1996 (The Japanes Pharmacopoeia, 13th ed. (1996), potassium iodide p. 578, sodium iodide p. 630) determine iodide with the ICl-method (J. Am. Chem. Soc. 25 (1903) 756-761; Z. Anorg. Chem. 36 (1903) 76-83; Fresenius Z. Anal. Chem. 106 (1936) 12-23; Arzneibuch-Kommentar, Wissenschaftliche Erläuterungen zum Europäischen Arzneibuch, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, Govi-Verlag - Pharmazeutischer Verlag GmbH, Eschborn, 12th suppl. (1999), K10 p. 2), using chloroform, which is toxic and hazardous to environment. Without the application of chlorinated hydrocarbons USP 2000 (The United State Pharmacopeia, 24th ed. (2000), potassium iodide p. 1368, sodium iodide p. 1535) and Brit 1999 (British Pharmacopoeia London, (1999), Appendix VIII C, p. A162) titrate iodide with the redox indicator amaranth. A titration with potentiometric indication giving two end-points at the step of I(2) and [ICl(2)](-) is described. Due to the high concentration of hydrochloric acid required for the ICl-method, the determination with DBH (1,3-dibromo-5,5-dimethylhydantoin; 1,3-dibromo-5,5-dimethyl-2,4-imidazolidinedione) can be recommended and is performed easily. Similarly, the iodide content of gallamine triethiodide may be analyzed with DBH by application of a visual two-phase titration in water and ethyl acetate or with potentiometric indication in a mixture of 2-propanol and water. During the removal of the excess of DBH 4-bromo-triethylgallamine (2,2',2"-[1-bromo-benzene-2,3,4-triyltris(oxy)]N,N,N-triethylethanium) is formed.

Hydantoins↗
PubMed1986

Relationship of dietary iodide and drinking water disinfectants to thyroid function in experimental animals.

The importance of dietary iodide on the reported hypothyroid effect of drinking water disinfectants on thyroid function was investigated. Previous studies have also showed differences in the relative sensitivity of pigeons and rabbits to chlorinated water. Pigeons and rabbits were exposed for 3 months to diets containing high (950 ppb) or low (300 ppb) levels of iodide and to drinking water containing two levels of chlorine. Results showed that the high-iodide diet prevented the hypothyroid effect observed in pigeons given the low-iodide diet and chlorinated drinking water. Similar trends were observed in rabbits exposed to the same treatment; however, significant hypothyroid effects were not observed in this animal model. The factor associated with the observed effect of dietary iodide on the chlorine-induced change in thyroid function is unknown, as is the relative sensitivity of rabbits and pigeons to the effect of chlorine. Several factors may explain the importance of dietary iodide and the relative sensitivity of these species. For example, the iodine formed by the known reaction of chlorine with iodide could result in a decrease in the plasma level of iodide because of the relative absorption rates of iodide and iodine in the intestinal tract, and the various types and concentrations of chloroorganics (metabolites) formed in the diet following the exposure of various dietary constituents to chlorine could affect the thyroid function. The former factor was investigated in the present studies. Results do not confirm a consistent, significant reduction in the plasma level of iodide in rabbits and pigeons exposed to chlorinated water and the low-iodide diet. The latter factor is being investigated.

Animals↗
PubMed2000

Induction of follicle formation in long-term cultured normal human thyroid cells treated with thyrotropin stimulates iodide uptake but not sodium/iodide symporter messenger RNA and protein expression.

Iodide uptake by the sodium/iodide symporter (NIS) in thyrocytes is essential for thyroid hormone production. Reduced NIS activity has been reported in thyroid diseases, including thyroid cancer and congenital hypothyroidism. The study of iodide uptake in thyrocytes has been limited by the availability of appropriate in vitro models. A new culture technique was recently developed that allows normal human thyroid primary culture cells to grow as monolayer cells and express differentiated functions for more than 3 months. We used this technique to study the effect of follicle formation and TSH on iodide uptake in these cells. Iodide uptake by the cells grown in monolayer was very low. Follicle formation was induced from monolayer cells, and electron micrographs demonstrated cell polarity in the follicles. No significant increase in iodide uptake was observed after TSH treatment of cells in monolayer or when follicle formation was induced without TSH. TSH stimulation of follicles, however, significantly increased iodide uptake ( approximately 4. 4-fold; P<0.001). Compared with iodide uptake in monolayers, the combination of follicle formation and TSH treatment stimulated iodide uptake synergistically to 12.0-fold (P<0.001). NIS messenger RNA (mRNA) and protein levels were almost the same in both monolayer cells and follicles. TSH treatment of monolayers and follicles produced significant (P<0.05) stimulation of mRNA ( approximately 4. 8- and approximately 4.3-fold respectively) and protein ( approximately 6.8- and 4.9-fold respectively). TSH stimulated NIS protein levels in both monolayer and follicles, however, stimulation of functional iodide uptake was only seen with TSH stimulation of follicles. The function of NIS may involve post-transcriptional events, such as intracellular sorting, membrane localization of NIS or another NIS regulatory factor. Polarized functions, such as iodide efflux into follicular lumina, may also contribute to the increased iodide concentration after follicle formation.

Carrier Proteins↗
PubMed2004

Kinetics of perrhenate uptake and comparative biodistribution of perrhenate, pertechnetate, and iodide by NaI symporter-expressing tissues in vivo.

UNLABELLED: Pertechnetate (as (99m)TcO(4)(-)), (123)I(-), and (131)I(-) have a long and successful history of use in the diagnosis and therapy of thyroid cancer, with uptake into thyroid tissue mediated by the sodium-iodide symporter (NIS). NIS has also emerged as a potential target for radiotherapy of nonthyroid malignancies that express the endogenous or transfected symporter. Perrhenates (as (188)ReO(4)(-) and (186)ReO(4)(-)) are promising therapeutic substrates of NIS, although less is known about their behavior in vivo. In this study, we endeavored to characterize the biologic behavior of perrhenate, especially in relation to iodide and pertechnetate, to better explore its possible therapeutic role. METHODS: We describe the simultaneous biodistribution and uptake in vivo of iodide, pertechnetate, and perrhenate in groups of healthy CD1 mice, either with or without coadministration of perchlorate (ClO(4)(-)), a potent NIS inhibitor. Animals administered single radiopharmaceuticals were imaged as a means of illustrating these findings. Kinetic properties of perrhenate were compared with those of iodide in a stably transfected NIS-bearing Madin-Darby canine kidney (MDCK) cell line. RESULTS: Biodistributions of iodide, pertechnetate, and perrhenate in live mice were remarkably similar. Activity in salivary gland and stomach was severalfold greater than in blood, remained elevated over the initial 2 h, and subsequently washed out. A similar pattern characterized pertechnetate and perrhenate uptake by the thyroid, in which the 2-h concentration was slightly more elevated than at the 20-min time point. However, uptake subsequently decreased by 19 h. In contrast, iodide continued to increase through the 19-h time point, presumably as a result of organification. The addition of perchlorate sharply decreased uptake of all 3 radiopharmaceuticals by the stomach, salivary glands, and thyroid and resulted in their rapid clearance, paralleling blood-pool clearance. In tissues that do not express NIS (liver, muscle, spleen), uptake of all 3 radiopharmaceuticals was low and rapidly decreased over time, paralleling blood-pool clearance. Similar findings were seen in kidney, where only minimal amounts of NIS are expressed in tubular cells. In stably transfected MDCK cells, steady-state accumulation of iodide was approximately 4-fold higher than that of perrhenate at 30 min. No active transport was demonstrated in nontransfected MDCK cell lines or after perchlorate administration. Uptake values measured at different concentrations of substrate demonstrated saturation kinetics. Apparent maximal velocity values for perrhenate and iodide were 25.6 +/- 1.4 and 106 +/- 3.2 pmol/ micro g, respectively, and corresponding affinity constant values were 4.06 +/- 0.87 and 24.6 +/- 1.81 micro mol/L. CONCLUSION: Perrhenate is avidly taken up by NIS in a manner similar to iodide and pertechnetate in vivo, with the exception of organification of iodide by the thyroid. By more fully appreciating the behavior of perrhenate, especially in relation to iodide and pertechnetate, we can better realize its potential role in the diagnosis and therapy of NIS-bearing tissues.

Animals↗
PubMed2000

Iodide excess induces apoptosis in thyroid cells through a p53-independent mechanism involving oxidative stress.

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 markedly. Inhibition of endogenous p53 activity did not affect the sensitivity of TAD-2 cells to iodide, and Western blot analysis demonstrated that p53, Bcl-2, Bcl-XL, and Bax protein expression did not change when cells were treated with iodide. These data indicate that excess molecular iodide, generated by oxidation of ionic iodine by endogenous peroxidases, induces apoptosis in thyroid cells through a mechanism involving generation of free radicals. This type of apoptosis is p53 independent, does not require protein synthesis, and is not induced by modulation of Bcl-2, Bcl-XL, or Bax protein expression.

Annexin A5↗
PubMed1998

The modulation of the human sodium iodide symporter activity by Graves' disease sera.

The transport of iodide into the thyroid, catalyzed by the Na+/I- symporter (NIS), is the initial and rate-limiting step in the formation of thyroid hormones. To study the basic characteristics of the human (h) NIS, we have established a Chinese hamster ovary cell line stably expressing the hNIS (CHO-NIS9). In agreement with previous work on the rat NIS, iodide uptake in these cells was initiated within 2 min of the addition of 131I, reaching a plateau after 30 min. Both perchlorate and thiocyanate inhibited iodide uptake in a dose-dependent manner, with inhibition evident at concentrations of 0.01 and 0.1 micromol/L, respectively, and reaching complete inhibition at 20 micromol/L and 500 micromol/L, respectively. Ouabain, which blocks the activity of the Na+/K+ adenosine triphosphatase, also inhibited iodide uptake in a dose-dependent manner, starting at concentrations of 100 micromol/L and reaching maximum inhibition at 1600 micromol/L, indicating that iodide uptake in these cells is sodium dependent. CHO-NIS9 cells were further used to study 88 sera from patients with Graves' disease, for iodide uptake inhibitory activity, which were compared with sera from 31 controls. Significant iodide uptake inhibition was taken as any inhibition in excess of the mean + 3 SD of the results with the control sera. On this basis, 27 (30.7%) of the Graves' sera, but none of the controls, inhibited iodide uptake in CHO-NIS9. IgGs from these patients also inhibited iodide uptake, indicating that this inhibitory activity was antibody mediated. In summary, we have established a CHO cell line stably expressing the hNIS and shown that antibodies in GD sera can inhibit iodide uptake in these cells. This further emphasizes the role of NIS as a novel autoantigen in thyroid immunity.

Animals↗
PubMed1988

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

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.

Animals↗
PubMed1987

Iodide-induced inhibition of adenylate cyclase activity in horse and dog thyroid.

The characteristics of the iodide-induced inhibition of cyclic AMP accumulation in dog thyroid slices have been previously described [Van Sande, J., Cochaux, P. and Dumont, J. E. (1985) Mol. Cell. Endocrinol. 40, 181-192]. In the present study we investigated the characteristics of the iodide-induced inhibition of adenylate cyclase activity in dog and horse thyroid. The inhibition of cyclic AMP accumulation by iodide in stimulated horse thyroid slices was similar to that observed in dog thyroid slices. The inhibition was observed in slices stimulated by thyroid-stimulating hormone, cholera toxin and forskolin. Increasing the concentration of the stimulators did not overcome the iodide-induced inhibition. Adenylate cyclase activity, assayed in crude homogenates or in plasma-membrane-containing particulates (100,000 x g pellets), was lower in homogenates or in particulates prepared from iodide-treated slices than from control slices. This inhibition was observed on the cyclase activity stimulated by forskolin, fluoride or guanosine 5'-[beta, gamma-imino]triphosphate, but also on the basal activity. It was relieved when the homogenate was prepared from slices incubated with iodide and methimazole. Similar results were obtained with dog thyroid. The inhibition persisted when the particulate fraction was washed three times during 1 h at 100,000 x g, in the presence of bovine serum albumin or increasing concentration of KCl. It was similar whatever the duration of the cyclase assay, in a large range of protein concentration. These results indicate that a stable modification of adenylate cyclase activity, closely related to the plasma membrane, was induced when slices were incubated with iodide. Iodide inhibition did not modify the affinity of adenylate cyclase for its substrate (MgATP), but induced a decrease of the maximal velocity of the enzyme. The percentage inhibition was slightly decreased when Mg2+ concentration increased, and markedly decreased when Mn2+ concentration increased. A detectable adenylate cyclase activity was demonstrated when intact slices were incubated in the presence of [alpha-32P]ATP, probably because of the presence of broken cells produced during the slicing. Iodide had no direct effect on this cyclase system, which confirms that iodide needs the integrity of the cell to induce the inhibition and suggests that the inhibition is not transmitted between cells.

Adenylyl Cyclase Inhibitors↗
PubMed1980

Intrathyroidally generated iodide: the role of propylthiouracil-sensitive processes in its production.

Thyroid radioiodide to serum radioiodide concentration (*T/*S) ratios 1 h after 131I administration were 3 times higher in rats pretreated with propylthiouracil (PTU) than in rats with binding thyroids. Although indications of a preponderance of transported iodide in the thyroid early after 131I injection were found, a reduction of the 1-h *T/*S ratio in TSH-treated rats by the inhibitor of iodotyrosine dehalogenation, mononitrotyrosine, points to an early contribution of intrathyroidally generated (internal) iodide to total thyroid iodide. In rat thyroids labeled 72 h earlier, there was no rise in electrophoretically separated radioiodide 2 h after the administration of PTU alone, but the elevation of thyroid iodide due to TSH was augmented by concurrently given PTU. On the assumption that PTU affects transported components of thyroid iodide identically whether they are labeled 1 or 72 h earlier, we conclude that PTU must severely depress the generation of internal iodide. This effect is no longer evident if TSH is given simultaneously. Further, our results are consistent with the hypothesis that internal iodide passes through a stage in which it is not available for organic binding before it mixes with transported iodide. TSH appears to facilitate the transfer of internal iodide into the pool which it shares with external iodide.

Animals↗
PubMed1981

Intrathyroidally generated iodide: the role of transport in its utilization.

Thyroid iodide labeled 72 h earlier with 131I was separated from organic iodine by polyacrylamide gel electrophoresis. The concentration of thyroid radioiodide was not significantly diminished 2 h after the administration of perchlorate (100 mg NaClO4) alone, but perchlorate reduced the rise in glandular radioiodide caused by simultaneously given TSH (1 IU). When propylthiouracil (PTU; 20 mg) was given along with it, perchlorate decreased thyroid radioiodide even in rats not treated with TSH. In rats given perchlorate, PTU caused a much slighter augmentation of the TSH-induced increase in the thyroid radioiodide concentration than in the absence of perchlorate. These results are interpreted as follows. Perchlorate-discharged iodide in rats not given TSH is largely transported iodide. Perchlorate can discharge intrathyroidally generated (internal) iodide too, but this is unequivocally reflected by a decrease in the thyroid iodide concentration only when the production of internal iodide is enhanced by TSH. Perchlorate in its own right interferes with organic binding of internal iodide, thereby partially preempting the effect whereby PTU causes accumulation of internal iodide in TSH-treated rats. We suggest that internal thyroid iodide is transported from its site of generation, the follicular cell, to its site of organic binding, the follicular lumen, by perchlorate-sensitive transport. It is also possible that internal iodide escaping from a follicle is conserved by perchlorate-inhibitable reuptake into follicular cells closer to the venous end of the capillary bed.

Animals↗
PubMed1990

Effect of hydrocortisone on the ability of thyrotropin to increase deoxyribonucleic acid synthesis and iodide uptake in FRTL-5 rat thyroid cells: opposite regulation of adenosine 3',5'-monophosphate signal action.

In FRTL-5 rat thyroid cells, hydrocortisone alters two TSH-increased cAMP-mediated activities in an opposite manner. Thus, in a concentration-dependent fashion, hydrocortisone synergistically enhances TSH-increased thymidine incorporation into DNA, whereas it inhibits TSH-induced iodide uptake. The effect of hydrocortisone on TSH-increased thymidine incorporation is specific, in that it has only a minimal ability by itself to increase thymidine incorporation into DNA and slightly inhibits the activity of insulin or insulin-like growth factor-I. The effect of hydrocortisone on TSH-induced iodide uptake does not result from altered iodide efflux, but, rather, from a decrease in the maximal velocity, not the Km, of iodide influx, i.e. from a decrease in the effective number of iodide porters. The action of a cAMP analog to increase thymidine incorporation into DNA or iodide uptake was also increased or decreased, respectively, by hydrocortisone, whereas hydrocortisone did not diminish the ability of TSH to increase cAMP levels in the cells. The different effect of hydrocortisone on these two cAMP-mediated activities reflects, therefore, regulation of cAMP signal action rather than the ability of TSH to generate a cAMP signal. Twenty-four hours after TSH, actinomycin-D superinduces iodide uptake and abolishes the action of hydrocortisone to inhibit iodide uptake. It has been suggested that actinomycin-D superinduces iodide uptake in FRTL-5 cells by a posttranscriptional action, inhibition of mRNA degradation, rather than by its known transcriptional actions linked to DNA synthesis. More recent studies of the effect of actinomycin-D, given under identical circumstances, on TSH-stimulated malic enzyme mRNA levels directly validate this hypothesis. We, thus, suggest that the opposite action of hydrocortisone on the two cAMP-mediated activities may reflect positive and negative regulation of the action of cAMP at different steps in the transduction process, one being transcriptional (DNA synthesis) and the other posttranscriptional (induction of iodide porter activity).

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Insulin and insulin-like growth factor-I inhibit thyrotropin-increased iodide transport in serum-depleted FRTL-5 rat thyroid cells: modulation of adenosine 3',5'-monophosphate signal action.

Insulin enhances the ability of TSH to induce iodide uptake in FRTL-5 rat thyroid cells maintained in 5% serum; however, in cells maintained in 0.2% serum, insulin inhibits the ability of TSH to induce iodide uptake. Since the inhibitory action of insulin is duplicated by 100-fold lower concentrations of insulin-like growth factor-I (IGF-I), inhibition appears to be mediated by the IGF-I receptor. Insulin and IGF-I inhibit the action of a cAMP analog to induce iodide uptake in a manner identical to TSH, but do not inhibit basal or TSH-increased cAMP levels; inhibition, thus, results from regulation of cAMP signal action rather than cAMP signal generation. Inhibition is associated with a more than 2-fold decrease in the maximum velocity of iodide influx, a less than 15% change in the rate of iodide efflux, and no change in the Km for iodide influx, i.e. inhibition effectively results from a decrease in the number of iodide porters. The inhibitory action of insulin/IGF-I is not additive with hydrocortisone, which, under the same conditions, also inhibits TSH- or cAMP-induced iodide porter activity. Actinomycin-D, given 24 h after TSH, superinduces TSH-induced iodide porter activity and abolishes the inhibition by insulin, IGF-I, and/or hydrocortisone; a similar paradoxical effect of actinomycin-D under these conditions has been explained by its ability to inhibit the action of a cAMP-induced factor that increases mRNA degradation. The inhibitory actions of insulin, IGF-I, and hydrocortisone on cAMP-induced iodide porter activity contrast with their simultaneous and synergistic stimulation of the transcriptional action of cAMP on DNA and thyroglobulin synthesis under these conditions.

Animals↗
PubMed1993

Clinical evaluation of the iodide/creatinine ratio of casual urine samples as an index of daily iodide excretion in a population study.

To assess the daily iodine intake in a population study, we have compared the validity and degree of reliability of the urine iodide/creatinine ratios and iodide concentrations of casual samples as a representative index of daily urine iodide excretion. The morning urine samples were obtained from apparently healthy 2,956 men and 1,182 women residing in Sapporo, Japan, and urine iodide was measured by an iodide selective electrode. The iodide/creatinine ratios was higher in women than in men, increasing more steeply with age in women than in men, due to a concomitant decrease in the urine creatinine level with age. The iodide concentration showed no age-related change. Similarly the daily urine iodide excretion measured in 22 control subjects by collecting 24-h urine specimens did not vary with age, while the iodide/creatinine ratio of these subjects increased with age. The correlation coefficient(r) of the iodide concentration with daily iodide excretion in the 95 observations of the 22 subjects was 0.832 (P < 0.001), higher than that of iodide/creatinine ratio with daily iodide excretion (0.699, P < 0.001). The 95% range of the iodide concentration in morning urine samples in the population (n = 4,138) was 9.0-70.3 mumol/L with a mean of 27.1 mumol/L.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗