Thyroidal radioiodine uptake and thyrotropic potency of the pituitary in a freshwater catfish,Mystus vittatus (Bloch), in response to L-thyroxin,antithyroid drugs,and heavy doses of 131I

Summary Experiments were conducted to ascertain the thyroidal ¹³¹I uptake and thyrotropic potency of the pituitary gland in a freshwater catfish, in response to L-thyroxine, antithyroid drugs and heavy doses of radioiodine. L-thyroxine treatments slightly lowered thyroidal radioiodine uptake, and there was at least a trend of lowered TSH content in the pituitaries of these animals. Administration of antithyroid drugs (propylthiouracil, thiourea, KSCN) caused a significant decrease in radioiodine uptake and a highly significant increase in TSH content of the pituitary. Heavy doses of I¹³¹ almost completely blocked thyroidal iodine uptake but they were as effective as antithyroid drugs in elevating TSH content of the pituitary.I am greatly indebted to Dr. G. E. Pickford, Yale University, U.S.A. for her helpful suggestions; to Dr. A. G. Sathyanesan, Banaras Hindu University, India, for encouragements; to Professor S. P. Ray-Chaudhuri, Banaras Hindu University, India, for providing laboratory facilities. I am also grateful to Baxtor Laboratories Inc., Morton Grove, Illinois, U.S.A. for the gift of Crystalline L-thyroxine which was made available through the courtesy of Professor Paul Starr and Dr. Thomas Garrett.     

Radioiodine: Biokinetics,mean dose and dose distribution

Summary For the radioiodine isotopes I-123, I-125, I-131, and I-132 the mean tissue dose and local dose distribution in the epithelial cells of a follicle have been calculated and compared to each other. Moreover, dose factors have been estimated for I-131 as a function of age considering age-dependent ingestion (milk consumption) and inhalation rates. Thereby, besides age-dependent biological half-times and thyroid masses, the thyroidal iodine uptake was assumed to be independent from age and taken to be about 1.7 the normal for an insufficient dictary iodine intake as in the Federal Republic of Germany.     

The nature of thyrotropin stimulation of thyroid function in Japanese quail: prolonged thyrotropin exposure is necessary to increase thyroidal 125I uptake

Single injections of thyrotropin (TSH) increase serum T4 and thyroidal 32P uptake but not thyroidal 125I uptake regardless of dosage, exposure time or age. Chronic TSH exposure, with 3 or more days of injection, does increase thyroidal 125I uptake. Studies using iodine (I) supplementation indicated that the increased thyroidal radioiodine uptakes seen with chronic TSH administration were not due to an I deficiency in the thyroid resulting from high hormone release. Labeled and unlabeled experiments comparing the effects of single vs. multiple injections of TSH were used to describe the effects of TSH on hormone release, hormone production and thyroidal I uptake.     

Effect of yogic exercises on thyroid function in subjects resident at sea level upon exposure to high altitude

Using radioactive iodine, the effect of 1 month's yogic exercises has been investigated on the thyroid function of subjects resident at sea level (SL) specially after their exposure to high altitude (HA). The results have been compared with a group of SL subjects who underwent physical training (PT) exercises for the same duration. Ten healthy male volunteers in the age range of 20–30 years were used as test subjects in this study with each serving as his own control. The subjects were randomly divided into two groups of 5 each. One group practised hatha yogic exercises, while the other group performed the regular PT exercises. The thyroidal accumulation and release of radioactive iodine have been measured in each of the subjects of both groups before and after 1 month of their respective exercises at SL. One month of yogic exercises at SL has been observed to cause a significant reduction in the trans-thy-roidal availability of radioiodine. The thyroid radioactivity in this group of subjects was always below normal levels with the exception of two peaks of radioactive iodine uptake, when the levels of radioactivity in the thyroid were similar to the control values of pre-yogic exercises. The release of radiolabel at 24–48 h was significantly increased after yogic exercises. In contrast, the subjects performing PT exercises for the same duration at SL showed significant thyroid uptake of radioactive iodine at 24 h. Subsequently their¹³¹I uptake continued to rise slowly until 72 h without any demonstrable thyroidal release of radiolabel. This indicated that increased thyroid activity was induced by conventional PT exercise. Exposure of SL residents to HA irrespective of their exercise regime altered the thyroidal handling of radioiodine. Thyroidal concentrations of freshly administered radioiodine at early and late sampling intervals were very high in both of the groups, especially the yogics, after their return to SL from HA. Possible mechanisms of the observed changes have been discussed.     

Influence of initial large dose on subsequent uptake of therapeutic radioiodine in thyroid cancer patients

Fifty-two patients with differentiated thyroid cancer, following thyroidectomy were studied by administering a quantity of up to 5 mCi of [¹³¹I]sodium iodide. In most of these patients, radioiodine uptake values obtained with the subsequent therapeutic dose were markedly lower than those observed with the initial doses. This observation was verified in seven of the patients with differentiated thyroid cancer, by measuring the radioiodine uptake with a second dose of 4.5 mCi of [¹³¹I]sodium iodide. Calculations showed that the major etiology was probably therapeutic irradiation of the thyroid by the first dose.     

Analysis of polypeptide disposition in human erythrocyte membranes employing membrane inversion

High resolution segregation of erythrocyte membrane polypeptides achieved by isoelectric focusing in 8 M urea was employed in conjunction with surface-restricted radioiodination to analyze the disposition of polypeptides within the human erythrocyte membrane. Several membrane polypeptides showed significant uptake of radioiodine, with the principal labeled component migrating between pH values of 3.0 and 3.5. Two approaches were taken in examining membrane polypeptide disposition on both faces of the erythrocyte membrane. Saturation labeling of the outer face of the membrane with one iodine isotope followed by cell lysis and re-iodination with a second iodine isotope did not prove feasible and another procedure based on surface iodination with ¹²⁵I, formation of sealed inside-out vesicles and re-iodination with ¹³¹I was adopted. Studies of sialic acid release from the membrane surface and trypsin cleavage of radioiodinated peptides indicated that selectively labeled, sealed inside-out vesicles had been formed. The ratio of ¹²⁵I to ¹³¹I in membrane polypeptides separated by isoelectric focusing confirmed the existence of externally disposed, internally disposed and spanning proteins.     

Compartmental models for human iodine metabolism

Compartmental models for the various aspects of human iodine metabolism are reviewed, emphasizing the role of Mones Berman in the development of this field. The review first presents published submodels for the peripheral distribution of inorganic iodine, for the thyroidal iodide trapping function, and for the peripheral distribution and metabolism of the thyroid hormones. Approaches to improving understanding of the physiology of the thyroid gland itself through compartmental modeling techniques are then discussed in more detail. The three submodels described above are incorporated into overall models of thyroid iodine metabolism after being simplified to various degrees. Previously published models for thyroid-gland radioiodine metabolism, as well as current work in progress, are illustrated by attempting to fit the models to data from a single (previously unpublished) detailed prolonged ¹²⁵I feeding experiment in a normal human subject. Published thyroid gland models reviewed include: (1) the usual presentation, where the thyroid is a single homogeneous iodine compartment; (2) the model of DeGroot and colleagues, where thyroidal iodine is presented as MIT, DIT, T3, and T4, each with an active and linked storage compartment; (3) the thyroid model developed by Berman and colleagues, with less chemical subcategorization but incorporating a delay compartment, in which a fraction of the iodinated material in the thyroid is partially or completely inaccessible to secretion during the delay; and the later updating of Berman's model to include a thyroidal iodide recirculation pool. The experimental data presented fits most of these models for the first 1–2 weeks, but the fit could not be extended to longer data collection times. To overcome this shortcoming, a new thyroid gland model is introduced. It is based on the latest Berman model but describes thyroglobulin metabolism as incorporating multiple delay compartments of various time periods. The overall fit of the long term data is better with this model construct than with any of the published models. It appears that a complex thyroidal substructure, such as that of the multidelay model under development, will be required to account for overall thyroid iodine metabolism as isotopic equilibrium in man is approached.     

Metabolism of 131I in relation to strobilation of Aurelia aurita L. (Scyphozoa)

The ¹³¹I isotope of iodine has been used to follow the uptake and metabolism of iodine during the process of strobilation in pre-conditioned polyps of Aurelia aurita L. Strobilating polyps accumulated free iodide from the media against a concentration gradient, the segmented portion of the polyps accumulating about three times as much as the basal portion. Almost all of the accumulated iodide appeared in the soluble portion of an acid-ethanol extract of polyp tissue as inorganic iodide. The time course of accumulation of iodine was not affected by previous exposure to either higher temperature or iodide. Inorganic iodide rather than organically bound iodine is thought to be the effective factor in the initiation of strobilation.     

Thyroid function and polyamines. III. Changes in ornithine decarboxylase activity and polyamine contents in the rat thyroid during hyperplasia and involution

Changes in ornithine decarboxylase (ODC) activity and in polyamine contents of the rat thyroid were studied under various experimental conditions. Methylthiouracil (MTU) treatment produced several-fold increases in the thyroid ODC activity and in the content of putrescine, spermidine and spermine within a week. While serum thyrotropin (TSH) levels increased gradually up to 3 weeks, the content of both putrescine and spermidine tended to reach a plateau after 2 weeks of the goitrogen treatment; spermine content continued to increase progressively for 3 weeks. Discontinuance of MTU at 7 days resulted in a rapid decline in the elevated thyroid ODC activity, followed by a diminution of putrescine, spermidine and RNA contents. Thyroidal putrescine, spermidine and RNA responded more sensitively to both introduction and withdrawal of TSH stimulation than thyroidal spermine and DNA. Excess iodide, having no effect on the basal level of thyroid ODC, suppressed the MTU-induced increase in this enzyme activity without affecting circulating TSH, thyroxine (T4) and triiodothyronine (T3) levels. There was a significant negative correlation between the ODC activity and intrathyroidal concentration of iodine in MTU-pretreated rats. Theophylline increased the thyroid weight and ODC activity when given to rats fed with a subeffective dose of MTU. Analyses of serum TSH, T4, T3 and of thyroidal iodine revealed that TSH-induced thyroid ODC activity was suppressed by increased circulating thyroid hormones and/or intrathyroidal iodine. Furthermore, it was suggested that thyroid hormones and excess iodide acted directly on the thyroid to alter polyamine biosynthesis, possibly by changing the responsiveness of the gland to TSH.     

Physical and radiobiological bases of the use of125I in the management of thyrotoxicosis

Increasing interest is recently shown in the use of¹²⁵I as an alternative isotope to¹³¹I for the management of thyrotoxicosis based on the postulate that there is a relative sparing of the reproductive integrity of the thyroid follicular cell and a consequent possibility of smaller incidence of hypothyroidism after therapy. A review of the dosimetric, radiobiological and clinical aspects of the use of¹²⁵I are presented here.For the same activity though¹²⁵I gives smaller mean glanddose than¹³¹I, the dose computations at microscopic level have revealed that there is a preferential irradiation of the apical membrane compared to the nucleus of the follicular cell. The ratio of the dose to the apical membrane and that to the nucleus increases with the decrease of the percentage colloid mass of the gland. Radiobiological significance of this non-uniform dose distribution across a follicular cell, with¹²⁵I, is brought out using rat thyroid as the biological system. For the same mean gland dose the follicular cell survival is larger with¹²⁵I than with¹³¹I. 24 h radioiodine uptake is reduced in case of¹²⁵I treatment whereas it is not affected with¹²⁵I. Pilot clinical trials using¹²⁵I for the management of thyrotoxicosis are underway in some centres. Preliminary results from centres using doses 3–4 times that of the conventional¹³¹I dose are not very different from those with conventional¹³¹I therapy. Centres that used doses same as or less than the conventional¹³¹I doses, reported smaller incidence of hypothyroidism.Alexander von Humboldt Fellow in Klinikum Steglitz, Berlin     

Synthesis, in vitro pharmacology and biodistribution studies of new PD 156707-derived ET(A) receptor radioligands

It is assumed that the regulation of cardiac endothelin (ET) receptor density is abnormal in heart diseases. From that perspective, an ET receptor radioligand is needed to assess ET receptor density in vivo. The nonpeptidyl ET(A) receptor antagonist PD 169390 was labelled with radioiodine to give a putative radioligand for SPECT. Labelling with [125I]iodide and [123I]iodide was accomplished with good to excellent radiochemical yields. The affinities of the nonradioactive reference and those of selected precursor compounds for ET(A) receptors were determined, using [125I]iodine labelled endothelin-1 with mouse ventricular membranes. All employed substances exhibited potent in vitro pharmacological characteristics with Ki values comparable to that of the lead compound PD 156707. Biodistribution studies and scintigraphic imaging experiments in mice, however, showed no significant uptake of the [123I] derivative in the heart.     

Synthesis of [3,5-125I]triiodo-l-thyronine of high specific activity

Two methods for the synthesis of [3,5-¹²⁵I]triiodo-l-thyronine of high specific activity are described. This triiodthyronine which carries the iodine label exclusively in the nonphenolic ring has not been available so far. Both methods start from [3,5-¹²⁵I]diiodo-l-thyronine which is iodinated either with iodine in potassium iodide or with iodide and chloramine T. The concentration of the iodinating agent is critical in both methods and the pH of the reaction mixture must be high enough (～11) to cause complete ionization of the phenolic group of the substrate. The triiodothyronine obtained in over 70% yield is purified by ion-exchange chromatography.     

Iodinated phospholipids and the iodination of proteins of dog thyroid gland in vitro

Slices of dog thyroid gland were incubated with liposomes consisting of (125)I-labelled phosphatidylcholine (the iodine was covalently linked to unsaturated fatty acyl chains). The (125)I label of (125)I-labelled liposomes was incorporated into thyroid protein and/or thyroglobulin at a higher rate than was the (131)I label of either Na(131)I or (131)I(2). The iodine was shown to be protein-bound by the co-migration of the labelled iodine with protein under conditions where free iodine, iodide and lipid-bound iodine were removed from protein. The uptake of iodine from the iodinated phospholipid was probably due to phospholipid exchange between the iodinated liposomes and the thyroid cell membrane, since (a) (14)C-labelled phospholipid was metabolized to (14)CO(2) and (b) many lipids in the tissue slice became (14)C-labelled. A very strong inhibition of iodide ;uptake' from Na(131)I, caused by thiosulphate, produced only a minor inhibition of the incorporation of (125)I from (125)I-labelled liposomes into thyroid protein and/or thyroglobulin. This implies that free iodide may not necessarily be formed from the iodinated phospholipids before their entrance or utilization in the cell. Synthetic polytyrosine polypeptide suspensions showed some iodination by (131)I-labelled liposomes. In tissues with low tyrosine contents, such as liver and kidney, only a trace uptake was observed. Salivary gland showed some uptake. Endoplasmic reticulum of thyroid gland showed a higher iodine uptake than that of the corresponding plasma membranes. These experiments, together with the demonstration of the diet-dependent presence of iodinated phospholipids in dog thyroid, leads us to suggest that iodination of the membrane phospholipids of thyroid cells may be directly or indirectly involved at some stage in the synthesis of thyroglobulin, or exists as a scavenger mechanism, to re-utilize and/or recover released iodine from unstable compounds inside the thyroid cell.     

The Normal Thyroidal Uptake of Iodine

The range of values for the 24-hour thyroidal accumulation of radioactive iodine in euthyroid persons varies with geographic location. In the San Bernardino Valley region of Southern California the “normal range” is 6 percent to 33 percent in euthyroid subjects. This is lower than in studies from other areas of the United States. The urinary iodide excretion and the absolute iodine uptake of the thyroid are higher than in studies from many other areas of the United States, pointing to iodine abundance as the reason for this difference. The geographic variation and the possibility of changing dietary iodine intake of normal persons point to the necessity of current and local determinations of the “normal range” of the thyroidal uptake of radioiodine if the results of this thyroid function test are to be properly interpreted.     

Radiation dose rates of differentiated thyroid cancer patients after <Superscript>131</Superscript>I therapy

Postoperative ¹³¹I treatment for differentiated thyroid cancer (DTC) can create a radiation hazard for nearby persons. The present prospective study aimed to investigate radiation dose rates in ¹³¹I-treated DTC patients to provide references for radiation protection. A total of 141 ¹³¹I-treated DTC patients were enrolled, and grouped into a singular treatment (ST) group and a repeated treatment (RT) group. The radiation dose rate of ¹³¹I-treated patients was measured. The rate of achieving discharge compliance and restricted contact time were analyzed based on Chinese regulations. Multivariate logistic regression analysis was used to analyze the independent factors associated with the clearance of radioiodine. The rate of achieving discharge compliance (¹³¹I retention <?400 MBq) was 79.8 and 93.7% at day 2 (D2) for the ST and RT groups, respectively, and reached 100% at D7 and D4, respectively. The restricted contact time with ¹³¹I-treated patients at 0.5 m for medical staff, caregivers, family members, and the general public ranged from 4 to 7 days. Multivariate logistic regression analysis showed that the 24-h iodine uptake rate was the only significant factor associated with radioiodine clearance. For the radiation safety of ¹³¹I-treated DTC patients, the present results can provide radiometric data for radiation protection.     

A radiotracer method to study efflux transport of iodide liberated from thyroid hormones via deiodination metabolism in the brain

AimsThyroid hormones (TH) play an important role in the development and functional maintenance of the central nervous system. The purpose of this study was to develop a radiotracer method for studying the in vivo efflux transport of iodide liberated by the TH metabolism in the brain. The rationale of our method is as follows: a radioiodinated compound can enter the brain and rapidly release iodide in situ; the iodide efflux rate can be estimated from the clearance of brain radioactivity after disappearance of the iodinated compound.Main methods6-[¹²⁵I]Iodo-9-pentylpurine ([¹²⁵I]9Pe6IP) was designed to enter the brain and release ¹²⁵I^? by the reaction with glutathione and synthesized from the corresponding bromo derivative in a Br/¹²⁵I exchange reaction. The brain kinetics of radioactivity and radioactive metabolites were investigated after intravenous injection of [¹²⁵I]9Pe6IP into mice. The iodide efflux rate was estimated in mice pretreated with perchlorate, an inhibitor of iodide transport from the brain.Key findingsHigh brain uptake (5.3% injected dose/g) was observed at 1 min, and almost complete conversion of [¹²⁵I]9Pe6IP to ¹²⁵I^? occurred 10 min after injection. The ¹²⁵I^? uptake from the blood was negligible. ¹²⁵I^? was eliminated from the brain along a single-exponential curve with a half-life of 6.0 min. Furthermore, dose-dependent inhibition of ¹²⁵I^? efflux was observed in mice pretreated with perchlorate.SignificanceWe conclude that 9Pe6IP labeled with ¹²⁴I (positron emitter) or ¹²³I (single-photon emitter) may be useful for studying the in vivo efflux transport of iodide in the brain using nuclear medicine imaging devices.     

Diurnal rhythms of thyroid hormones in rooster chicks (Gallus domesticus). 1. Studies on the colloid epithelium portion, the radioiodine accumulation in the thyroid gland and the plasma radioiodide concentration]

Four and five week old White Leghorn cockerels were investigated concerning diurnal changes of thyroidal activity. They were kept under normal conditions, including the changes in day light (light from 5.00 am to 8.00 pm). In the thyroid maxima of the per cent amount of colloid were found at 3.00 am and at noon. The values differed significantly from the intermediate ones (2P less than 0.001) which reached only 22 per cent of the maxima. The thyroidal uptake of radioiodine had also a maximum at 3.00 am (51 percent and 78 percent resp., 90 min. or 24 hours p.i.). The 24-h uptake at 3.00 am was significant different from the corresponding uptakes between 6.00 am and 6.00 pm (53-61 percent; 2P less than 0.05). The plasma radioiodide increased at afternoon and in the evening. The 9.00 pm concentration differed significantly from the 9.00 am concentration (2P less than 0.001). Since in the afternoon most of the food is ingested the thyroid can take up a greater amount of untracered iodide and therefore the radioiodide concentration of plasma may remain high. The above observations may be explained in the following way: (1) The thyroidal iodine uptake is increased in the afternoon corresponding to the increase in colloid; however these increase is not detectable by measuring the radioiodine uptake because of dilution effects (during the night the increase in colloid coincidences with the increase in iodine uptake); (2) looking at the daily changes of colloid and radioiodine uptake the thyroid may be stimulated in the early morning and in the evening.     

Methodical optimization of redioiodine uptake experiments in living rats

The paper deals with the estimation of thyroidal uptake of 131I in living rats. The animals are fixed in a specially marked glass tube. This tube is discontinuously moved over a scintillation counter within a lead collimator. Counts of 131I are estimated segmentically. The highest counts ratio with the geometrical factor of the appropriate segment is used to calculate the thyroidal radioiodine uptake. Similar results, obtained with an 131I-source placed in various segments of the top side of glass tube, indicate that the uptake values obtained in this manner exact. Thyroidal uptake values, which were received on living rats with this method (in vivo) and compared with values obtained with the prepared and plated thyroid of the same rats (in vitro) show a very high correlation (r = 0,99; p greater than 0,001). In repeated estimations of the thyroidal 131I-uptake on one animal a variation coefficient of 1.5% (n = 13) was obtained. The advantage of this in vivo method is the possibility to determine the thyroidal activity at various times after 131I-application (2 phase test) and by repeated 131I-applications under different conditions (diet, age, for instance).     

Some quantitative aspects of the labelling of proteins with 125I by the iodine monochloride method

The labelling of proteins by the iodine monochloride method was studied by using a mathematical model. The equations used were primarily derived from the mass law equation of the isotopic exchange reaction between [¹²⁵I]iodide and iodine monochloride. For convenient application, all equations were programmed into a computing desk-top calculator. To support the validity of the theoretical model, a series of iodinations of insulin were performed under various labelling conditions. The results of these experiments compare well with the theoretically derived values. Deviations from the theoretical values occurring at molar ratios of [¹²⁵I]iodide to iodine monochloride < 0.1 and > 4.0 are explained and suggestions made about how to prevent them. The mathematical model was used to simulate the isotopic exchange, and the iodination reaction under various conditions, to study (a) the influence of the amount of [¹²⁵I]iodide on the amount of [¹²⁵I]iodine monochloride formed, (b) the influence of the specific radioactivity of [¹²⁵I]iodide on the amount of [¹²⁵I]iodine monochloride formed, and (c) the influence of the specific radioactivity of [¹²⁵I]iodide on the number of millicuries needed for labelling to a desired extent.     

Nuclear factor-kappa B inhibition can enhance apoptosis of differentiated thyroid cancer cells induced by 131I

Objective

To evaluate changes of nuclear factor-kappa B (NF-κB) during radioiodine 131 (¹³¹I) therapy and whether NF-κB inhibition could enhance ¹³¹I-induced apoptosis in differentiated thyroid cancer (DTC) cells in a synergistic manner.

Methods

Three human DTC cell lines were used. NF-κB inhibition was achieved by using a NF-κB inhibitor (Bay 11-7082) or by p65 siRNA transfection. Methyl-thiazolyl-tetrazolium assay was performed for cell viability assessment. DNA-binding assay, luciferase reporter assay, and Western blot were adopted to determine function and expression changes of NF-κB. Then NF-κB regulated anti-apoptotic factors XIAP, cIAP1, and Bcl-xL were measured. Apoptosis was analyzed by Western blot for caspase 3 and PARP, and by flow cytometry as well. An iodide uptake assay was performed to determine whether NF-κB inhibition could influence radioactive iodide uptake.

Results

The methyl-thiazolyl-tetrazolium assay showed significant decrease of viable cells by combination therapy than by mono-therapies. The DNA-binding assay and luciferase reporter assay showed enhanced NF-κB function and reporter gene activities due to ¹³¹I, yet significant suppression was achieved by NF-κB inhibition. Western blot proved ¹³¹I could increase nuclear NF-κB concentration, while NF-κB inhibition reduced NF-κB concentration. Western blot also demonstrated significant up-regulation of XIAP, cIAP1, and Bcl-xL after ¹³¹I therapy. And inhibition of NF-κB could significantly down-regulate these factors. Finally, synergism induced by combined therapy was displayed by significant enhancements of cleaved caspase 3 and PARP from Western blot, and of Annexin V positively staining from flow cytometry. The iodine uptake assay did not show significant changes when NF-κB was inhibited.

Conclusion

We demonstrated that ¹³¹I could induce NF-κB activation, which would attenuate ¹³¹I efficacy in DTC cells. NF-κB inhibition by Bay 11-7082 or by p65 siRNA transfection was effective in suppressing NF-κB regulated anti-apoptotic changes and in combined regimen apoptosis was achieved synergistically.