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PubMed2003

Enhanced iodide transport after transfer of the human sodium iodide symporter gene is associated with lack of retention and low absorbed dose.

Transfer of the sodium iodide symporter (hNIS) has been proposed as a new principle of cancer gene therapy. Using clinically relevant doses of (131)I for the treatment of NIS-expressing prostate carcinoma cells, we investigated the kinetics and the absorbed doses obtained in these tumors. hNIS-expressing cell lines accumulated up to 200 times more iodide when compared to wild-type cells. However, a rapid efflux of the radioactivity (80%) occurred during the first 20 min after replacement of the medium. In rats, the hNIS-expressing tumors accumulated up to 20 times more iodide when compared to contralateral transplanted wild-type tumors. After 24 h and doses of 550, 1200 or 2400 MBq/m(2) hNIS-expressing tumors lost 89, 89 and 91% of the initial activity, respectively. Dosimetric calculations showed that 1200 MBq/m(2) resulted in 3+/-0.5 Gy (wild-type tumor 0.15+/-0.1 Gy) and 2400 MBq/m(2) resulted in 3.1+/-0.9 Gy (wild-type tumor 0.26+/-0.02 Gy). Although transduction of the hNIS gene induces iodide transport in rat prostate adenocarcinoma a rapid efflux occurs, which leads to a low absorbed dose in genetically modified tumors. With regard to a therapeutic application additional conditions need to be defined leading to iodide trapping.

Absorption↗
PubMed1987

Congenital hypothyroidism from complete iodide transport defect: long-term evolution with iodide treatment.

Hypothyroidism from iodide transport deficiency is a rare disease, especially when found in two affected siblings. Treatment with high doses of iodide has been recommended, but no long term results have been reported. Two siblings with congenital hypothyroidism due to total failure to transport iodide have been followed up during twelve and a half years of treatment with oral potassium iodide. Iodine doses varied between 10.3 and 22 mg/day, and serum total iodine concentrations between 100 and 210 micrograms/dl. Total triiodothyronine (T3), thyroxine (T4) and free T4 were in the normal range during the time of study. Basal thyroid stimulating hormones (TSH) and maximum TSH response to thyrotrophin releasing hormone (TRH) were also in the range of normal values. These data along with clinical findings confirmed the potential usefulness of iodine in hypothyroidism due to complete iodide transport defect.

Adolescent↗
PubMed1988

Inhibition by iodide of iodide binding to proteins: the "Wolff-Chaikoff" effect is caused by inhibition of H2O2 generation.

H2O2 generation is limiting the oxidation and binding to proteins of iodide. In dog thyroid slices thyrotropin and carbamylcholine greatly enhance protein iodination and H2O2 generation. The action of thyrotropin is mimicked by dibutyryl cyclic AMP and forskolin which suggests that it is mediated by cyclic AMP. The action of carbamylcholine was mimicked by ionomycin and by phorbol myristate ester. This suggests that the effect of carbamylcholine is mediated by the two intracellular signals generated by the Ca++ phosphatidylinositol cascade: Ca++ and diacylglycerol. The Wolff-Chaikoff effect is the inhibition by iodide of its own organification. In dog thyroid slices, iodide greatly inhibited H2O2 generation stimulated by thyrotropin and by carbamylcholine. Iodide decreased the production of intracellular signals induced by TSH and carbamylcholine but it also inhibited the action of probes of these intracellular signals (dibutyryl cAMP, forskolin, ionomycin, phorbol-myristate ester) on the H2O2 generating system itself. These effects were suppressed by methimazole an inhibitor of iodide oxidation.

Animals↗
PubMed1989

EDTA inhibits peroxidase-catalyzed iodide oxidation through interaction at the iodide binding site.

EDTA inhibits the formation of I3- from iodide catalysed by various pure peroxidases. The inhibition is concentration-dependent and chloroperoxidase (CPO) is more sensitive than horseradish peroxidase (HRP) and lactoperoxidase (LPO). EDTA is more active than EGTA or other biological chelators tested. Zn2+, Mn2+ and Co2+ are equally active in reversing the effect of EDTA on both CPO and HRP almost completely, but ineffective in the case of LPO. The effect of EDTA on HRP can be reversed by a higher concentration of iodide but not by H2O2. EDTA causes a hypsochromic change in the absorption of the Soret band of HRP at 402 nm, and iodide can reverse this effect. EDTA can effectively displace radioiodide specifically bound to HRP. It is suggested that EDTA inhibits iodide oxidation by interacting at the iodide binding site of the HRP.

Chloride Peroxidase↗
PubMed2006

From the molecular characterization of iodide transporters to the prevention of radioactive iodide exposure.

In the event of a nuclear reactor accident, the major public health risk will likely result from the release and dispersion of volatile radio-iodines. Upon body exposure and food ingestion, these radio-iodines are concentrated in the thyroid, resulting in substantial thyroidal irradiation and accordingly causing thyroid cancers. Stable potassium iodide (KI) effectively blocks thyroid iodine uptake and is thus used in iodide prophylaxis for reactor accidents. The efficiency of KI is directly related to the physiological inhibition of the thyroid function in the presence of high plasma iodide concentrations. This regulation is called the Wolff-Chaikoff effect. However, to be fully effective, KI should be administered shortly before or immediately after radioiodine exposure. If KI is provided only several hours after exposure, it will elicit the opposite effect e.g. lead to an increase in the thyroid irradiation dose. To date, clear evaluation of the benefit and the potential toxicity of KI administration remain difficult, and additional data are needed. We outline in this review the molecular characterization of KI-induced regulation of the thyroid function. Significant advances in the knowledge of the iodide transport mechanisms and thyroid physiology have been made. Recently developed molecular tools should help clarify iodide metabolism and the Wolff-Chaikoff effect. The major goals are clarifying the factors which increase thyroid cancer risk after a reactor accident and improving the KI administration protocol. These will ultimately lead to the development of novel strategies to decrease thyroid irradiation after radio-iodine exposure.

Animals↗
PubMed2003

Influence of iodide and iodolactones on thyroid apoptosis. Evidence that apoptosis induced by iodide is mediated by iodolactones in intact porcine thyroid follicles.

Iodine induced thyroid involution is caused by apoptosis rather than necrosis. This effect of iodide on apoptosis of thyroid epithelial cells may be not a direct one but mediated by iodinated derivatives i.e. of polyunsaturated fatty acids, especially of iodolactones, which have previously shown to inhibit thyroid cell proliferation. We studied the influence on apoptosis of iodide (2 microM and 20 microM) and iodolactone (0.05 microM and 0.5 microM), with and without TSH (1 mU/ml), using a well characterized ex vivo- culture system of intact porcine thyroid follicles in three-dimensional culture. Apoptosis and necrosis was evaluated by electron-microscopy. Stimulation with 2 and 20 microM iodide rapidly induced a rate of apoptosis (4 - 6 %) comparable to about 40-fold lower doses of delta-iodolactone (0.05 microM and 0.5 microM). Addition of TSH (1 mU/ml) caused a slight but not significant further increase of the incidence of apoptotic cells. The rate of necrotic thyroid epithelial cells (1 - 2 %) was similar in all experiments. As delta-iodolactone in very low concentrations--comparable to iodide in higher concentrations--not only inhibits growth but also induces apoptosis, it has to be supposed that the effect of iodide is mediated by this iodinated compound. However, further experiments are necessary to confirm this hypothesis. In addition it could be demonstrated, that apoptosis is a very rapid and limited process in intact follicles. This also may explain, why iodine supplementation even in high doses does not lead to thyroid atrophy but only normalisation of thyroid size. These results confirm that apoptosis is an important regulated and limited mechanism in goiter involution.

Animals↗
PubMed2004

Lack of correlation for sodium iodide symporter mRNA and protein expression and analysis of sodium iodide symporter promoter methylation in benign cold thyroid nodules.

Cold thyroid nodules (CTNs) are characterized by a reduced iodide uptake in comparison to normal thyroid tissue. The sodium iodide symporter (NIS) is the first step in thyroid hormone synthesis and mediates the active iodide transport in the thyroid cells suggesting that decreased iodide uptake could be a result of changes in NIS expression or molecular defects in the NIS gene. In contrast to previous studies, an intraindividual comparison of NIS mRNA expression in CTNs and their corresponding surrounding tissue was performed using direct detection of NIS mRNA. A significant reduction in NIS mRNA expression was detected in 86% of the 14 investigated CTNs. We hypothesized that human sodium iodide symporter (hNIS) transcriptional failure could be caused by primary molecular NIS gene defects and/or methylation of DNA in the NIS promoter. However, no mutation in the NIS cDNA nor in the NIS promoter region upstream up to-443 bp from the ATG start codon was detected. Therefore, primary molecular NIS gene defects were excluded. However, in 50% of CTNs with reduced NIS mRNA expression, the promoter region was hypermethylated. NIS mRNA expression in these hypermethylated CTNs only reached a maximum of 30% of the corresponding surrounding tissue. Hence, methylation of CpG islands in the NIS promotor could be a regulatory mechanism of NIS transcription in CTNs. Immunoblot revealed absent hNIS protein expression in the total cell membrane fraction in 45% of investigated nodules. In the majority of the remaining CTNs NIS protein expression was decreased in the nodule tissue compared to the corresponding surrounding tissue. For investigating protein expression immunhistochemistry has two advantages. First, the whole nodule area can be investigated, and second, NIS expression can be detected in areas where an immunoblot of a cell membrane fraction is negative. Interestingly, immunhistochemistry revealed higher NIS expression in 50% of CTNs compared to their corresponding surrounding tissues and NIS staining was predominantly intracellular. These data demonstrate that NIS protein expression does not reflect NIS mRNA expression. Therefore, factors that affect targeting of NIS to the plasma membrane are likely to be affected.

Blotting, Western↗
PubMed1995

The G2M arrest caused by iodide is unrelated to the effects of iodide at adenylate cyclase.

Previously, we have shown that the iodide was able to inhibit TSH induced thyrocyte proliferation by arresting the cell cycle at G0G1 and G2M, suggesting that the iodide may be exerting its effects through more than the TSH-adenylate cyclase-cAMP system. To confirm the effects of iodide on the adenylate cyclase (AC) system, forskolin- and dibutyryl-cyclic-AMP (dBcAMP)-stimulated FRTL5 thyroid cells were exposed to inhibitory concentrations of iodide and the resultant effects on the cell cycle were compared to the effects observed with TSH, using flow cytometric DNA analysis. Forskolin stimulated the proliferation of FRTL5 cells in a dose-dependent manner. Cell numbers rose from baseline by 169 +/- 4% to peak at 10 microM forskolin. Interestingly, 100 microM forskolin inhibited cell proliferation, causing cell numbers to fall by approximately 50%. Iodide inhibited forskolin-induced proliferation to baseline levels. However, the pattern of cell cycle perturbation was different to that with TSH-stimulated cells. There were no differences in the proportion of cells in G0G1 between forskolin alone and forskolin + NaI, while there was a marked fall in the proportion of cells in S phase, indicating possible partial arrest at G0G1. Furthermore, there was a marked accumulation of cells in G2M over and above that found with TSH + NaI, indicating arrest at G2M. dBcAMP maximally stimulated cell numbers to rise from baseline by 125% with 1 mM dBcAMP. Again, higher concentrations of the mitogen had an inhibitory effect on proliferation. The addition of NaI inhibited dBcAMP stimulated cell proliferation.

Adenylyl Cyclases↗
PubMed2003

Predicting fetal perchlorate dose and inhibition of iodide kinetics during gestation: a physiologically-based pharmacokinetic analysis of perchlorate and iodide kinetics in the rat.

Perchlorate (ClO4-) disrupts endocrine homeostasis by competitively inhibiting the transport of iodide (I-) into the thyroid. The potential for health effects from human exposure to ClO4- in drinking water is not known, but experimental animal studies are suggestive of developmental effects from ClO4- induced iodide deficiency during gestation. Normal hormone-dependent development relies, in part, on synthesis of hormones in the fetal thyroid from maternally supplied iodide. Although ClO4- crosses the placenta, the extent of inhibition in the fetal thyroid is unknown. A physiologically-based pharmacokinetic (PBPK) model was developed to simulate ClO4- exposure and the resulting effect on iodide kinetics in rat gestation. Similar to concurrent model development for the adult male rat, this model includes compartments for thyroid, stomach, skin, kidney, liver, and plasma in both mother and fetus, with additional compartments for the maternal mammary gland, fat, and placenta. Tissues with active uptake are described with multiple compartments and Michaelis-Menten (M-M) kinetics. Physiological and kinetic parameters were obtained from literature and experiment. Systemic clearance, placental-fetal transport, and M-M uptake parameters were estimated by fitting model simulations to experimental data. The PBPK model is able to reproduce maternal and fetal iodide data over five orders of magnitude (0.36 to 33,000 ng/kg 131I-), ClO4- distribution over three orders of magnitude (0.01 to 10 mg/kg-day ClO4-) and inhibition of maternal thyroid and total fetal I- uptake. The model suggests a significant fetal ClO4- dose in late gestation (up to 82% of maternal dose). A comparison of model-predicted internal dosimetrics in the adult male, pregnant, and fetal rat indicates that the fetal thyroid is more sensitive to inhibition than that of the adult.

Animals↗
PubMed2005

Modeling chlorite-iodide reaction dynamics using a chlorine dioxide-iodide reaction mechanism.

The mechanism of Lengyel, Li, Kustin, and Epstein (J. Am. Chem. Soc. 1996, 118, 3708) for the oscillatory chlorine dioxide-iodide reaction accurately models the reaction in closed and open systems. We investigated whether this mechanism minus the single reaction involving chlorine dioxide models the chlorite-iodide reaction equally well. It agrees qualitatively with clock reaction results. As for open system dynamics, the mechanism predicts the existence of two steady states and bistability in very nearly the same regions where these features are found experimentally in the pH range 2-4. A discrepancy in the range of bistability emerges as pH decreases, and it cannot be remedied by taking into account chlorous acid decomposition. That we were unable to locate an oscillatory region is of greater significance. Because the chlorite-iodide reaction is sensitive to mixing effects, we incorporated a two-parameter model of imperfect mixing but still found no oscillations at physically reasonable parameter values. These discrepancies strongly suggest that to obtain predictive utility for the chlorite-iodide reaction, revision of the chlorine dioxide-iodide mechanism is required.

Journal Article↗
PubMed1994

Dissociation of thyrotropin-dependent enzyme activities, reduced iodide transport, and preserved iodide organification in nonfunctioning thyroid adenoma and multinodular goiter.

Several biochemical and functional modifications demonstrated in goitrous tissues could reflect the effect of goitrogenic factors. Growth-enhancing agents, including TSH itself, have been involved in goitrogenesis. To study comparatively the variation patterns of some TSH-dependent enzymes within single goitrous tissues, we measured the activities of peroxidase (TPO), NADPH-cytochrome-c (cyt-c) reductase, and monoamine oxidase (MAO) in tissues from cold follicular adenoma and multinodular goiter. Iodide transport and organification were also evaluated. Perinodular and necropsy tissues were used as controls. The mean TPO activity measured by guaiacol as well as triiodide assays was significantly increased in multinodular goiter, whereas a nonsignificant increment was observed in cold adenoma. NADPH-cyt-c reductase and MAO were markedly increased in the two types of pathological tissues. The individual activities of the three enzymes showed dissimilar modifications within single samples and among different tissues. There was no correlation in the activities of the enzymes within single specimens from cold adenoma and multinodular goiter, except for MAO and NADPH-cyt-c reductase in multinodular goiter, for which a significant correlation was obtained. In this tissue, MAO and TPO measured by guaiacol assay were weakly correlated. TPO activity evaluated by guaiacol oxidation was correlated with that measured by triiodide formation in cold adenoma, but not in multinodular goiter. The mean iodide organification values assayed by iodotyrosine formation in the absence of exogenous H2O2 in particulate fractions from cold adenoma and multinodular goiter were within the normal range. A reduced iodide transport, evaluated as the thyroid/medium ratio, was observed in slices from these tissues. The dissociation of the three enzyme activities in single specimens from cold adenoma and multinodular goiter along with the reduced iodide transport in these tissues support the hypothesis that factors other than TSH or with TSH-like effects could be involved in the abnormal thyroid growth.

Adenoma↗
PubMed2002

Pendrin is an iodide-specific apical porter responsible for iodide efflux from thyroid cells.

The Pendred syndrome gene encodes a 780-amino acid putative transmembrane protein (pendrin) that is expressed in the apical membrane of thyroid follicular cells. Although pendrin was shown to transport iodide and chloride using Xenopus laevis oocytes and Sf9 insect cells, there is no report using mammalian cells to study its role in thyroid function. We show here, using COS-7 cells and Chinese hamster ovary cells transfected with expression vectors encoding sodium iodide symporter or human Pendred syndrome gene cDNA and by comparison with studies using rat thyroid FRTL-5 cells, that pendrin is an iodide-specific transporter in mammalian cells and is responsible for iodide efflux in the thyroid.

Animals↗
PubMed1992

1,25-Dihydroxycholecalciferol attenuates thyrotropin stimulated iodide accumulation in rat thyroid follicular FRTL-5 cells by reducing iodide porter number.

We have recently shown that rat thyroid follicular FRTL-5 cells have functional receptors for 1,25-dihydroxycholecalciferol (1,25- (OH)2D3) and that 1,25-(OH)2D3 attenuates the thyrotropin (TSH) induced iodide uptake. Here we show that the dibutyrylcyclic AMP induced iodide uptake was significantly reduced by 1,25-(OH)2D3, indicating that 1,25-(OH)2D3 affects the cAMP signal pathway beyond cAMP generation. The Vmax of the iodide porter was significantly reduced in 1,25-(OH)2D3 treated cells as compared to cells treated with TSH alone, indicating that 1,25-(OH)2D3 reduces the effective number of iodide porters in FRTL-5 cells.

Animals↗
PubMed1984

Iodide organification defect in a cold thyroid nodule: absence of iodide effect on cyclic AMP accumulation.

A follicular adenoma of the thyroid was 'hot' one hour after 99mTc pertechnetate administration, but 'cold' 24 h after 131I iodide administration. Incubation of the tissue in vitro demonstrated a defect in iodide binding to proteins that was abolished by addition of an H2O2 generating system. In this tissue iodide failed to inhibit TSH-induced cyclic AMP accumulation. The results show that iodide oxidation is required for its inhibitory action on cyclic AMP accumulation in human thyroid.

Adenoma↗
PubMed1987

Complete iodide trapping defect in two cases with congenital hypothyroidism: adaptation of thyroid to huge iodide supplementation.

Two cases of congenital defect in iodide trapping mechanism are related. The absence of thyroid and gastric concentration of 99mTcO4 led to the diagnosis. The study of saliva and gastric:serum concentration ratios confirmed the complete defect. The kinetics of radioiodine studied by external detection showed an early simultaneous decay in the thyroid, the stomach and the left ventricle. Thyroid accumulation of 131I, demonstrated by camera imaging, was estimated to be 0.1% at 48 h. It probably originated from simple diffusion. Iodide supplementation was progressively increased to 4.5 g and 10 g day-1 respectively. It resulted in a normalization of all parameters. Huge doses of iodide did not result in any evidence of hyperthyroidism as TSH rose normally after TRH. Intermittent iodide supplementation in one case could not maintain euthyroidism longer than a few weeks. Daily treatment, therefore, seems necessary.

Adolescent↗
PubMed1984

[A case of iodide myxedema observed for 3 years under a low iodide diet--especially on the restoration of the mechanism of escape from the Wolff-Chaikoff effect].

A 47-year-old housewife was admitted to our hospital because of general fatigue and constipation suggesting hypothyroidism. For 3 years before admission, general fatigue, arrhythmia, dry skin, drowsiness, cold intolerance and hypermenorrhea occurred insidiously. She had habitually taken considerable amounts of seaweed every day, e.g. more than 50 g of " Kombu " for more than 5 years and at least 1 g of " Wakame " for 6 months. On admission, serum thyroxine (T4) was 1.3 micrograms/dl, serum triiodothyronine (T3) was 47 ng/dl, TSH was 132 microunits/ml, and 123I thyroidal uptake was 60% at 3 hr. and 75% at 24 hr. Anti-thyroglobulin hemagglutination antibodies and anti-thyroid microsomal hemagglutination antibodies were both negative. When seaweed was omitted from her diet, T4 rose to 6.3 micrograms/dl and T3 rose to 113 ng/dl, whereas TSH lowered to 11 microunits/ml in 2 weeks. The seaweed-free diet was continued and 4 months later, when she had become euthyroid, an open biopsy of the thyroid gland was carried out. Histological examination of the specimen revealed a marked colloid deposition without characteristic features of Hashimoto's disease. Five months after admission, with the daily administration of 100 mg potassium iodide (KI), the effects of inorganic iodide on thyroid function had begun to be seen. On the 16th day of the KI regimen, palpitation and tachycardia (pulse rate 160/min.) with multifocal ventricular premature beat appeared, and T4 on the 11th day was 5.9 micrograms/dl, which was clearly lower than the pretreatment level of 8.4 micrograms/dl. KI was discontinued on the 16th day, and one week after the withdrawal, T4, T3 and TSH all returned to the pretreatment level. For more than 3 years on a seaweed-free diet, she remained euthyroid without any thyroid regimen. To see the effects of inorganic iodide on thyroid function after this long period on a seaweed-free diet, KI was again administered. One hundred mg/day KI for 14 days followed by 200 mg/day for 21 days had virtually no effect on T4, T3 and free T4 and she remained well. None of the perchlorate discharge tests performed on 3 occasions during the 6 month period after the initiation of the seaweed-free diet showed a discharge.(ABSTRACT TRUNCATED AT 400 WORDS)

Female↗
PubMed2003

The rat sodium iodide symporter gene permits more effective radioisotope concentration than the human sodium iodide symporter gene in human and rodent cancer cells.

Expression of the sodium iodide symporter (NIS) gene in tumor cells may provide a novel mechanism for treating cancer. The NIS mediates the normal physiological transport of iodide across the thyroid cell membrane. This mechanism of iodide uptake has been used to both diagnose and treat thyroid cancer. Tissue expression of the NIS is largely limited to the thyroid; therefore, expression of the NIS gene in cancer cells would allow for specific iodine uptake, radioisotope accumulation, and treatment. In this study, we directly compared the human and rat NIS (rNIS) for their ability to concentrate radioisotope into human and rodent cancer cells. Perchlorate-sensitive (125)I uptake in multiple cell lines was demonstrated following transduction with retroviral vectors expressing either the human or rNIS gene. Surprisingly, iodine uptake was consistently higher with the rNIS gene, up to 5-fold greater, when compared to the human gene, even within a variety of human tumor cell lines. This iodine uptake allowed for cell killing following (131)I treatment in NIS-transduced cells when assayed by in vitro clonogenic assays. These results demonstrate that the rNIS gene provides superior iodine uptake ability, and may be preferable for use in designing anticancer gene therapy approaches.

Animals↗
PubMed2004

Expression of the apical iodide transporter in human thyroid tissues: a comparison study with other iodide transporters.

Iodide transport by thyrocytes involves two transporters, namely the Na(+)/I (-) symporter located at the basolateral pole and possibly pendrin in the apical membranes of the cell. Recently, we identified a human gene and its protein product, designated hAIT, as a putative new transporter involved in iodide transfer across the apical membrane of thyrocytes. In the present report, we analyzed both hAIT gene and protein expressions in a large series of benign and malignant human thyroid tissues. Using immunohistochemistry, hAIT staining was detected in normal thyroid tissue in about 10% of follicles; in positive follicles, 10-40% of thyrocytes, mostly the tall cells, were stained. In thyroid tissues obtained from patients with Graves' disease and toxic adenomas, hAIT mRNA and protein levels were similar to those found in normal tissue. In hypofunctioning adenomas, hAIT mRNA levels were slightly decreased, and apical iodide transporter (AIT) immunostaining was similar to that observed in normal thyroid tissue. AIT staining was stronger in Hürthle cell adenomas and in microfollicular adenomas. In thyroid carcinomas, the mean and median hAIT mRNA levels were significantly decreased. Expression of AIT protein was undetectable in most papillary carcinomas and was weak but detectable in most follicular carcinomas; it was negative in anaplastic carcinomas.

Adenoma↗