Antithyroid Effect Research Articles

Antithyroid and goitrogenic effects of millet: role of C-glycosylflavones.

Pearl millet [Pennisetum millet (L.) leeke] is the main source of food energy for the rural poor in many areas of the semiarid tropics. Epidemiological evidence suggests that millet may play a role in the genesis of endemic goiter in these areas, and sparse experimental data in rats support this suspicion. This study was undertaken to determine in vivo in rats and in vitro using porcine thyroid slices and a thyroid peroxidase (TPO) assay the goitrogenic and antithyroid effects of millet diets, extracts of millet, and certain pure compounds contained therein. For use in these studies, whole grain millet was progressively dehulled to yield successively four bran and four flour fractions in which direct analyses revealed progressively lower concentrations of C-glycosylflavones. In vivo feeding of bran fraction 1, that richest in C-glycosylflavones, led to a significant increase in thyroid weight and antithyroid effects. Feeding of bran fraction 2, the next richest in C-glycosylflavones, produced similar, but less marked, changes. In vitro studies of 125I metabolism using porcine thyroid slices indicated that extracts of bran fractions 1 and 2 were most potent, producing changes similar to those produced by methimazole (MMI). At a concentration of 60 mumol/L, glucosylvitexin, the major C-glycosylflavone present in millet, had effects comparable to those of 1 mumol/L MMI. Similarly, in studies of porcine TPO, extracts of bran fraction 1 caused pronounced (85%) inhibition of enzyme activity, and progressively less inhibition was induced by extracts of bran fractions 2, 3, and 4. Overall, the TPO-inhibiting activities of the various millet fractions closely correlated with their C-glycosylflavone concentrations. Three C-glycosylflavones present concentrations. Three C-glycosylflavones present in millet, glucosylvitexin, glycosylorientin, and vitexin, also inhibited TPO activity. Thus, in vivo and in vitro studies revealed that millet diets rich in C-glycosylflavones produce goitrogenic and antithyroid effects similar to those of certain other antithyroid agents and small doses of MMI. We conclude that in areas of iodine deficiency in which millet is a major component of the diet, its ingestion may contribute to the genesis of endemic goiter.

Effect of mouth rinsing with two polyvinylpyrrolidone-iodine mixtures on iodine absorption and thyroid function.

A prospective study was conducted to investigate the effect of long term therapy with two iodine-containing mouth rinses on thyroid function. Two groups of subjects were treated daily for 6 months with either a 5% polyvinylpyrrolidone (PVPI)-1.5% H2O2 mixture (Perimed) or a 5% PVPI-water mixture. Thyroid function studies, serum iodine concentrations, and urinary iodine excretion were measured before treatment, at 6-week intervals during the 6-month treatment period, and 3 weeks after the last treatment. There was evidence of significant iodine absorption (elevated serum total iodine and inorganic iodide concentrations and urinary iodine excretion) from daily use of both Perimed and the PVPI-water mixture. Serum T3 and T4 concentrations and the free T4 index did not change. There was a small significant rise in serum TSH concentrations during mouth rinse therapy, but all values remained within the normal range. This small increase in serum TSH is a normal adaptive response to the antithyroid effect of increased iodine intake and accounts for the maintenance of normal serum T4 and T3 concentrations. While daily use of these iodine-containing mouth rinses does result in significant iodine absorption, there is no evidence for the development of thyroid dysfunction during a 6-month course of therapy.

Effects of oral erythrosine (2′,4′,5′,7′-tetraiodofluorescein) on thyroid function in normal men

Erythrosine (Er), a tetraiodinated derivative of fluorescein, is a coloring agent widely used in foods, cosmetics, and pharmaceutical products. Because of its high iodine content and previous reports demonstrating an inhibitory effect of eythrosine on hepatic 5′-monodeiodination, we studied the effects of this compound on thyroid function and serum and urinary iodide concentrations in normal subjects. Thirty normal men, equally divided into three treatment groups, each received a 14-day course of oral Er in doses of 20, 60, or 200 mg/day. Serum thyroxine (T4), triiodothyronine (T3), reverse T3 (rT3), thyroid stimulating hormone (TSH), protein-bound iodide (PBI), and total iodide concentrations, serum T3-charcoal uptake, and 24-hour urinary iodide excretion were measured on Days 1, 8, and 15. Thyrotropin-releasing hormone (TRH) tests were performed on Days 1 and 15. There were no significant changes in serum T4, T3, rT3, and T3-charcoal uptake values at any dose. In men receiving 200 mg Er/day, the mean basal serum TSH concentration increased significantly from 1.7 ± 0.1 (SE) on Day 1 to 2.2 ± 0.1 μU/ml on Day 15 ( p < 0.05), and the mean peak TSH increment after TRH increased from 6.3 ± 0.5 to 10.5 ± 1.0 μU/ml ( p < 0.05). There were no significant changes in basal or peak TSH responses in the men receiving 20 or 60 mg Er/day. Significant dose-related increases in serum total iodide and PBI concentrations occurred during all three doses, and significant dose-related increases in urinary iodide excretion occurred during the 60 and 200 mg/day Er doses. These data suggest that the increase in TSH secretion induced by Er was related to the antithyroid effect of increased serum iodide concentrations, rather than a direct effect of Er on thyroid hormone secretion or peripheral metabolism.

Duration of antithyroid action of methimazole estimated with an intravenous perchlorate discharge test.

We have used a method based on a perchlorate discharge test to estimate the duration of antithyroid effect of two doses of methimazole (MMI). Six patients with diffuse toxic goitre took 5 mg MMI twice daily and six took 20 mg twice daily over the study period of 12 weeks. Biochemical control of hyperthyroidism was achieved in all patients and thyroid hormone supplementation was required by all of the patients in the higher dose group to avoid hypothyroidism. Discharge of radioiodine from the thyroid by perchlorate diminished in both groups with time after MMI. After 5 mg MMI, perchlorate discharge as a percentage of the 30-min uptake (mean +/- SD), was 81.7 +/- 3.3% at 2.2 h, 69.3 +/- 18.9% at 5.9 h, 22.6-23.4% at 13.4 h and 2.7-6.7% at 25.1 h. After 20 mg MMI, the discharge was 92.5 +/- 1.9% at 2.2 h, 84.3 +/- 8.8% at 6.3 h, 64.8 +/- 24.1% at 13.3 h and 26.9-29.4% at 25.1 h. Only four patients (one in the lower dose group) showed a detectable discharge at 25 h and one of the patients treated with the lower dose showed no discharge at 13 h. These estimates of the effect of MMI on thyroidal iodide organification are not in keeping with published thyroidal MMI concentrations which do not show a fall between 3-6 h and 17-20 h after carbimazole. The explanation for this disparity is not clear but may be based on a redistribution of thioureylenes within the thyroid with time after dosage.(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid function in a cassava-eating population affected by epidemic spastic paraparesis.

Thyroid function was studied in a rural population in Mozambique that had been affected by an epidemic of spastic paraparesis attributed to dietary cyanide exposure from cassava. Laboratory investigation on a sample of this population demonstrated very high levels of serum and urinary thiocyanate, indicating a heavy exposure to cyanide. The urinary excretion of iodine was within normal limits, indicating an adequate intake of iodine. The serum levels of FT4I were somewhat decreased and serum FT3I, T3/T4 ratio and TSH were somewhat raised. This hormone pattern suggests an adaptation to the antithyroid effect of thiocyanate, but not overt hypothyroidism. A follow-up study on school children was performed, and it also demonstrated high thiocyanate exposure, adequate intake of iodine, and absence of endemic goitre. The results show that if iodine supply is adequate, the thyroid gland is capable of adaptation to a heavy body burden of thiocyanate without development of overt hypothyroidism or goitre.

Antithyroid effects of propylthiouracil and sulfamonomethoxine in rats and monkeys

Experiments were performed to investigate the species difference in antithyroid effects of propylthiouracil (PTU) and sulfamonomethoxine (SMM). Sprague-Dawley rats were administered 30 mg/kg of PTU, or 30 or 270 mg/kg of SMM orally for 5 weeks, while squirrel monkeys received 30 mg/kg of PTU or 270 mg/kg of SMM. In rats receiving 30 mg/kg of PTU, a decrease of both serum 3,5,3′-triiodothyronine and thyroxine concentrations and of 131I incorporation into the thyroid hormone precursors was observed, together with elevation of serum thyroid-stimulating hormone concentration, an increase in thyroid weight, and hyperplasia of the follicular epithelium of the thyroid gland. Similar changes were seen in rats receiving 270 mg/kg of SMM; however, the antithyroid effects of SMM were less severe than those of PTU. No change was produced in monkey thyroids by 5-week treatments with 30 mg/kg of PTU or with 270 mg/kg of SMM. The molar concentration of PTU required for the in vitro inhibition of thyroid peroxidase was markedly lower in rats than in monkeys. SMM showed a similar species difference in the inhibition of thyroid peroxidase in vitro, but the enzyme inhibition of SMM was weaker than that of PTU. These findings suggest that rats were more sensitive to the antithyroid effects of PTU and SMM than monkeys, and that inhibition of thyroid peroxidase may play an important role in species difference in the antithyroid effects of the two drugs.

Thyroid disease, behavior, and psychopharmacology

The authors review psychiatric complications of thyroid disease and the use of psychotropic agents in hyper- and hypothyroid patients. Neuropsychiatric symptoms of hyperthyroidism tend to resolve with treatment of excessive thyroid production; those of hypothyroidism respond in a variable manner to thyroid replacement, but most patients improve substantially after becoming euthyroid. The judicious use of most psychotropics has its place even in the presence of overt thyroid disease. The important antithyroid effects of lithium should be noted when treating patients with thyroid disease. Routine monitoring of thyroid function in otherwise healthy patients taking antipsychotic agents, tricyclic antidepressants, or monoamine oxidase inhibitors (MAOIs) is not believed necessary.

Effect of thiocyanate levels In milk on thyroid function in iodine deficient subjects

To utilize the antibacterial effect of the lactoperoxidase system to prevent bacterial spoilage of raw milk it is necessary to increase the thiocyanate concentration of the milk. Thiocyanate has, however, a potent antithyroid effect which is enhanced by iodine deficiency. In this study the thyroid function has been studied, before and after 4 weeks daily administration of 250 ml of such treated milk, in 55 goitrous subjects living in an endemic goiter region of western Sudan. The iodine content was 0.1 mg/l and the thiocyanate content was either 3.6 mg/l (n 19) or 19 mg/l (n 36) in the milk. At the start of the experiment all subjects were iodine deficient with a urinary excretion of 40-50 micrograms/g creatinine. After 4 weeks daily intake of 4.75 mg of thiocyanate by way of milk the serum thiocyanate level increased by approximately 1.7 mg/l. Both at the beginning and at the end of the experimental period the serum levels of thyroxine, triiodothyronine and TSH were in the normal range for all subjects. After 4 weeks the TSH levels had decreased significantly, (from 2.6 +/- 0.2 to 2.1 +/- 0.2 mU/l, p less than 0.001) probably as an effect of the supplementary intake of iodine. The thyroid hormone levels remained unchanged during the experimental period. In conclusion, the intake of milk with an iodine concentration of 0.1 mg/l and a thiocyanate concentration of 19 mg/l does not have a negative effect on the thyroid function in iodine deficient subjects.

Effects of fluoride on thyroid hormone biosynthesis. Studies in a highly sensitive test system.

In view of the recommendation that fluoride supplements via drinking water or table salt prevent dental caries, we analyzed whether fluoride had antithyroid properties in a sensitive experimental model. Rats were given either 60 or 200 micrograms/ml fluoride in the drinking water. This raised the serum fluoride concentration from 0.165 to 0.246 in the first and to 0.576 micrograms/ml in the second instance. Although the higher fluoride dose was near the toxic range, no antithyroid effect was observed. Neither organification of iodine, nor any subsequent step of thyroid hormone biosynthesis (transformation of monoiodotyrosine to diiodotyrosine and then to thyroxine) were affected. Fluoride had no effect on thyroglobulin content of the thyroid gland or on the degree of iodination of thyroglobulin.

β-Adrenergic Antagonist Inhibition of Hepatic 3,5,3′-Triiodothyronine Production*

beta-Adrenergic antagonists provide moderate symptomatic relief for most hyperthyroid patients, although these agents have no direct antithyroid effects. Propranolol administration results in modest declines in serum T3 concentrations in both hyperthyroid and normal subjects and also inhibits T4 to T3 conversion in various tissue preparations in vitro. Other beta-adrenergic antagonists have not been shown to consistently alter serum T3 concentrations in vivo or T3 production in vitro. To evaluate the ability of beta-adrenergic antagonists to inhibit T4-5'-deiodination, we measured T3 production from T4 in rat liver homogenates (10,000 X g supernatant) using 1 microM T4 in the presence of varying concentrations of the beta-adrenergic antagonists available in the United States. Each drug inhibited T3 production, and the dose-dependent responses were linear and parallel when plotted as percent inhibition vs. log dose concentration. The calculated drug concentrations required to produce 50% inhibition were: propranolol, 1.7 mM; pindolol, 6.7 mM; timolol, 11.5 mM; atenolol, 23.2 mM; metoprolol, 30.5 mM, and nadolol, 106.1 mM. The IC50 values were similar in the presence of 4 mM dithiothreitol. In separate studies, the ability of D- and L-propranolol to inhibit T3 production was compared with that of D,L-propranolol, the common form. Both D- and L-propranolol were as effective as the racemic mixture. The propranolol metabolites 4-hydroxypropranolol, 4-methylpropranolol, propranolol glycol, and N-desisopropyl propranolol were also effective inhibitors. Thus, beta-adrenergic antagonists inhibit T3 production in vitro. This inhibition is not related to beta-adrenergic antagonism per se, but is correlated with the lipid solubility of the drugs, which may explain the effects of propranolol on serum T3 in vivo.

Intake of thiocyanate by way of milk and its possible effect on thyroid function

The keeping quality of milk can be improved if the lactoperoxidase system is activated. To make such an activation efficient the thiocyanate concentration has to be increased. Since, however, thiocyanate has a potent antithyroid effect, thyroid function has been studied in 37 healthy individuals during 12 wk of daily intake of 8 mg thiocyanate by way of milk. The thiocyanate increased significantly in serum and reached a maximum value after 4 wk (+3.8 mg/ 1). The increased serum levels coincided with an increased excretion in urine (+4.8 mg/g creatinine). The levels of thyroxine, triiodothyronine, and thyrotropic hormone were all in the normal range at the beginning of the investigation and no significant changes were found during the experimental period. In conclusion, a daily intake of 8 mg thiocyanate by way of milk does not have any apparent effect on the thyroid function.

Antithyroid effect of chlorpropamide?

1 The relationship between plasma chlorpropamide concentration and thyroid function was examined in 87 maturity onset diabetic patients receiving chronic therapy. 2 Although plasma chlorpropamide concentration was weakly negatively correlated with serum thyroxine (r = 0.33, P less than 0.01) the mean serum thyroxine and thyrotrophin (TSH) were not different from that of a matched control group of diabetics treated with diet alone. 3 Serum thyroxine was negatively correlated with the duration of diabetes in both groups. 4 These results suggest that chlorpropamide does not have a clinically significant antithyroid effect.

Antithyroid effect of 2,3-dihydroxypyridine in vivo and in vitro.

AbstractThe antithyroid effect of 2,3-dihydroxypyridine (2,3-DHP) was investigated in vivo and in vitro. Thyroid studies were carried out on two groups of rats; one group of 14 rats were fed a low-iodine diet containing 1% 2,3-DHP for 25 days, and a control group of 12 rats received low-iodine diet alone. 2,3-DHP-treated rats had reduced thyroid function with a significant rise in serum thyrotropin (TSH) levels and decreased serum triiodothyronine (T3) levels; thyroxine (T4) and T3 contents of the thyroid gland were 20 and 10%, respectively, lower than those of controls. In vitro, 2,3-DHP inhibited peroxidase activity, and its antiperoxidase potency was similar to the commonly used thioureylene antithyroid drug, propylthiouracil. In addition, 2,3-DHP was a much weaker inhibitor of the thyroid conversion of T4 to T3 in vitro than propylthiouracil. 2,3-DHP represents a new class of antithyroid drug and its main action appears to be inhibition of peroxidase-catalyzed thyroid hormone formation in the thyroid ...

Correlation between antithyroid effect and serum concentrations of propylthiouracil in patients with hyperthyroidism.

1 Correlation between the kinetics of propylthiouracil and its antithyroid effect was studied in 17 hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of hyperthyroid patients. The serum concentration of propylthiouracil 1 h after an oral dose of 400 mg of the drug was used as kinetic parameter as this concentration from the previous study was found to correlate significantly (r = 0.84, P less than 0.01) with the area under the serum concentration-time curve. 2 After 3 weeks of treatment with 200 mg propylthiouracil three times daily the serum concentration of propylthiouracil was correlated to the decrease in various thyroid parameters such as total and free indexes of serum thyroxine, triiodothyronine and reverse triiodothyronine. 3 Significant correlations were found between the serum concentration of propylthiouracil and all the measured thyroid variables except reverse triiodothyronine. The highest degree of correlation was obtained between serum propylthiouracil and the percentage decrease in total and free indexes of triiodothyronine (r = 0.63 and 0.70, respectively, P less than 0.01). 4 It is suggested that a serum concentration of propylthiouracil above 4 to 5 micrograms/ml 1 h after an oral dose of 400 mg of the drug will secure a sufficient and rapid antithyroid effect during continuous therapy.

Direct protection against acetaminophen hepatotoxicity by propylthiouracil. In vivo and in vitro studies in rats and mice.

Hepatotoxicity caused by acetaminophen can be prevented by enzyme-catalyzed conjugation of its reactive metabolite with glutathione (GSH). Since we have shown in previous studies that 6-N-propyl-2-thiouracil (PTU) can substitute for GSH as a substrate for the GSH S-transferases, we examined the possibility that PTU might also protect against acetaminophen hepatotoxicity by direct chemical interaction with the reactive metabolite of acetaminophen. In an in vitro system consisting of [(3)H]acetaminophen, liver microsomes from phenobarbital-pretreated rats, and an NADPH-generating system, we found that PTU had a dose-dependent additive effect with GSH on inhibition of acetaminophen covalent binding. PTU administration also resulted in a dose-dependent decrease in both GSH depletion and covalent binding in vivo in acetaminophen-treated mice. To examine the possible mechanisms by which PTU exerts its protective effect, we studied the action of PTU on both acetaminophen conjugation and metabolic activation. PTU had no effect upon acetaminophen pharmacokinetics in phenobarbital-pretreated rats, as examined by measuring acetaminophen concentration in bile, urine, and blood after an intraperitoneal dose, nor did it alter the total amount of polar conjugates formed. Microsomes from PTU-treated rats were unaltered in cytochrome P-450 concentrations and p-nitroanisole-O-demethylase, benzo-alpha-pyrene hydroxylase, and cytochrome c-reductase activities. Furthermore PTU did not decrease acetaminophen-GSH adduct formation in vitro, suggesting that there was no reduction in drug activation. However, in bile from [(35)S]PTU and [(3)H]acetaminophen treated rats, as well as in incubates of the two drugs with liver microsomes, a new (35)S- and (3)H-containing product could be identified. By both thin layer chromatography and high pressure liquid chromatography this new product, which co-eluted with [(3)H]acetaminophen, was separated from unreacted [(35)S]PTU. The formation of this product in vitro was a function of PTU concentration and reached a maximum of 0.06 mumol/min per mg protein at 0.5 mM PTU. In vivo, the total biliary excretion of this product over 4 h (116 nmol) equaled the net reduction in acetaminophen metabolite covalent binding in the liver of phenobarbital-pretreated rats (108 nmol). We conclude that PTU, independent of its antithyroid effect, diminishes hepatic macromolecular covalent binding of acetaminophen reactive metabolite both in vivo and in vitro, and it does so by detoxifying the reactive metabolite through direct chemical interaction in a manner similar to GSH. These observations may define the mechanism by which PTU is protective against liver injury caused by acetaminophen.

Antithyroid effect of a food or drug preservative: 4-hydroxybenzoic acid methyl ester.

4-hydroxybenzoic acid methyl ester (methylparaben) inhibits organification of iodide by isolated hog thyroid cells. The concentration which produces a 50% inhibition was about 2.0×10−4M. A similar inhibition was observed in nonstimulated and TSH- or dibutyryl cyclic AMP-stimulated cells. Neither iodide uptake nor cyclic AMP generation were altered by methylparaben.

Effect of Thiourea on Intracranial Bone Tumour Formation in AkR Mice

The effect of administration of thiourea (5 g/kg in diet) alone or simultaneously with thyroxine (1 mg/l in drinking water) on the frequency of hyperplastic benign osteoma of the skull was studied in AkR mice. Animals treated with both thiourea and thyroxine were in hyperthyroidism: the thyroxine dose received was higher that that required to prevent thiourea-induced thyroid gland hypertrophy. A significant increase of the intracranial bone tumour (IBT) frequency was observed both in mice treated with thiourea alone and those which received thiourea and thyroxine simultaneously. Increase of IBT frequency was not due to the antithyroid effect of thiourea but seems due to a direct toxic action of thiourea on the pituitary.

Further studies of the action of antithyroid drugs on Mycobacterium leprae.

SummaryMethimazole, an antithyroid drug, and thiambutosine, an antimicrobial active against M. leprae in the mouse, were both found to inhibit multiplication of M. leprae in the mouse foot pad when administered in concentrations too small to inhibit thyroid function of the mice. Moreover, methimazole inhibited multiplication in vitro of a number of cultivable Mycobacteria. Although the antimicrobial and the antithyroid effects may be exerted through a common mechanism, it appears that methimazole nevertheless possesses direct antimicrobial properties.

Sensitivity to lithium in treated Graves' disease: effects on serum T4, T3 and reverse T3.

Seven patients judged to be euthyroid following treatment of diffuse toxic goiter were studied to determine if they were susceptible to lithium induced hypothyroidism. Lithium carbonate was administered for 4-7 weeks in a dosage (900 mg/day) which maintained serum lithium levels between 0.5-1.0 mEq/l. Blood was obtained weekly for the determination of serum 3,5,3'-triiodothyronine (T3), thyroxine (T4), 3,3',5'-TRIIODO-L-thyronine (reverse T3, rT3) and thyrotropin (TSH). Values observed during lithium therapy were compared to those obtained prior to, and approximately one week after discontinuing lithium. During the pretreatment preiod, mean (+/- SE) serum T3, T4, and rT3 concentrations were 130 +/- 21 ng/100 ml, 7.6 +/- 0.4 mug/100 ml and 48 +/- 8 ng/100 ml, respectively, and decreased during lithium administration with the lowest T3, T4 and reverse T3 concentrations of the lowest T3, T4 and reverse T3 concentrations of 92 +/- 8 ng/100 ml, 4.9 +/- 0.6mug/100 ml, and 33 +/- 6 ng/100, ml, respectively, being reached between the fourth and sixth weeks of study. Thereafter, and in spite of continued treatment with lithium, values for serum concentrations of T3, T4, and rT3 plateaued, or actually increased in 4, 6, and 5 subjects, respectively. Serum TSH concentrations remained 3.0 muU/ml or less throughout the study in 6 patients; 2 of these subjects had no TSH response to thyrotropin-releasing hormone (TRH), even though they had been euthyroid for 3 and 10 months. These data suggest that patients euthyroid following treatment of diffuse toxic goiter display sensitivity to the antithyroid effects of lithium. Furthermore, these observations support the thesis that the inhibitory effects of lithium and iodine upon thyroid hormone synthesis or secretion may involve a similar mechanism of action since increased thyroidal iodine content may be a consequence of therapy with either agent.

Evaluation of dietary rapeseed protein concentrate flours in rats and dogs

Two high-protein concentrate flours made from rapeseed ( Brassica spp.) were fed to growing dogs and rats for 90 days in semisynthetic diets. The oxazolidinethione concentrations of the two types of flour were of the order of 0.287 and 0.02 mg/g. In each experiment, 20 and 40% of the total dietary protein was supplied by the rapeseed flour (RSF); the balance was supplied as casein. Control groups received only casein. Only a low order of antithyroid activity was detected in the flours used. Measures of thyroid 131I uptake, serum thyroxine concentration, thyroid weight, and histology remained essentially normal. Serum glutamic-pyruvic transaminase activity was decreased by RSF, while packed cell volume and erythrocyte counts increased in the rats. No treatment-associated abnormalities were noted in the dogs. It was concluded that the antithyroid effects of the RSF used in this study were substantially reduced compared to the RSF used in other studies.