Effects Of Propylthiouracil Research Articles

The Effects of Propylthiouracil and Other Drugs on the Uptake of 75Se-Selenomethionine by the Pancreas

The influence of pre-treatment with a variety of agents on the uptake of 75Se-selenomethionine by the rat pancreas has been studied. The agents ranged from thyroid hormones to protein synthesis inhibitors but out of 16 tested, only propylthiouracyl (50 mg/kg i.p. administered for 3 days prior to 75Se-methionine injection) resulted in a significant increase in the pancreatic uptake (17%) and in the pancreas liver concentration ratio (25%). Seven of the agents resulted in significant reductions in the pancreas/liver concentration ratios. No significant effects were produced by the addition of carrier methionine or selenomethionine (in the range 10-250 micrograms/kg body weight) to the injected radiopharmaceutical. It was concluded that many factors may influence the uptake, but that the interrelationship of hypothalamus, pituitary and pancreas is of particular interest.

Effect of propylthiouracil on nycthemeral and sex related variation of plasma TSH in rats.

Studies of the effect on feedback mechanisms in nycthemeral fluctuation of plasma TSH and of its sex-related variation were carried out on normally fed (Purina) and propylthiouracil (PTU) treated rats. Plasma TSH concentration of purina fed rat was significantly higher in males than in females (M = 96 +/- 14, F = 49 +/- 3 microunits/ml, P less than 0.01). Plasma T4 concentration also showed a high tendency in males compared to females (M = 7.4 +/- 0.5, F = 5.8 +/- 1.0 micrograms/dl, 0.05 less than P less than 0.1) but the statistical difference was not significant. Plasma TSH demonstrated a typical periodicity characterized by a zenith at 1200 hr and a nadir at 1800 hr as in the previous reports. Plasma TSH concentrations rose apparently after the diet was switched to the one containing 0.15% of PTU. On the other hand, plasma T4 concentrations decreased to the very low levels following PTU administration. Concerning to the nycthemeral fluctuation and its sex related variation following PTU administration, nycthemeral fluctuation in male rats disappeared rapidly, whereas it was preserved in female rats. These facts showed that it kept more persistent fluctuation in female rats than in male rats under the high plasma TSH levels. Furthermore, female rats showed higher concentration of plasma TSH after PTU treatment compared to male rats. These results suggest that the nycthemeral fluctuation of plasma TSH was abolished or masked by the feedback mechanism of hypothalamo-pituitary-thyroid axis and there was a sex-related difference.

The effect of propylthiouracil and temperature on avian thyroid activity

High ambient temperatures cause a reduction in thyroid gland size of chickens but propylthiouracil (PTU) treatment produces an increase in gland size regardless of temperature. This increase in size after PTU treatment during high temperature is evident after 7 days of PTU treatment but not after 14 days of treatment. Cyclic AMP-dependent protein kinase is activated in the thyroid gland with PTU treatment during high temperatures with no alteration in activity in the pituitary. These results suggest that the pituitary is not activated by TRH during periods of high ambient temperature and the thyrotrophs may release TSH in direct response to lowered serum thyroid levels produced by PTU treatment.

Influence of Thyroid Status on Lipid Metabolism in the Perfused Rat Liver

Thyroid disease is often accompanied by changes in the concentrations of serum lipids and lipoproteins. To evaluate the hepatic contribution to the serum abnormalities in thyroid disease, we examined fatty acid metabolism in perfused livers from pair-fed rats made hypothyroid with propylthiouracil (PTU) or made hyperthyroid by treatment with triiodothyronine (T(3)). The animals treated with T(3) became hyperphagic, depending on dose of drug and duration of hyperthyroidism. It was necessary, therefore, for appropriate controls, that food intake of T(3)-treated rats be restricted to quantities consumed by euthyroid rats. Animals treated with PTU for 2 wk became hypophagic, and therefore, food consumption of controls was restricted to that eaten by rats receiving PTU. Dependent on dose of T(3) and duration of treatment, the output of triglyceride and glucose was diminished, whereas output of ketone bodies was increased by livers from hyperthyroid animals. In contrast, livers from PTU-treated animals secreted increased amounts of triglyceride and glucose, whereas ketogenesis was diminished. The best models for study proved to be animals treated with either 10 mug T(3)/100 g body wt per d or 1 mg PTU/100 g body wt per d for 7 d. Under these conditions, all animals consumed the same quantity of food as did the euthyroid rats, but continued to display the metabolic alterations outlined above. The effects of PTU on hepatic metabolism were readily reversible by simultaneous administration of T(3). It is clear from these data that the thyroid status of the rat regulates hepatic triglyceride formation and secretion, and ketogenesis.

Lipid and carbohydrate metabolism in euthyroid and hypothyroid chick embryo ( Gallus domesticus)

1. 1. The effect of propylthiouracil (PTU)-induced hypothyroidism on carbohydrate and lipid metabolism was studied in the chick embryo. 2. 2. A single dose of PTU (250 μg/embryo) was administered on day 11 and embryos sacrificed on day 20 of incubation. 3. 3. Thyroid glands were significantly enlarged (6 fold) by PTU administration. 4. 4. Increased thyroid weight was associated with growth retardation and decreased plasma thyroxine levels. 5. 5. Plasma glucose level was lower and phospholipids were significantly higher in the hypothyroid embryo. 6. 6. Liver lipid concentrations in the control and hypothyroid embryos were not different but were significantly higher in both groups when compared to previously reported values in the young chick. 7. 7. In contrast to PTU treatment after hatching, liver glycogen levels were not increased in the hypothyroid chick embryo. This was attributed to the high lipid nutrient condition of the chick embryo since a high lipid diet in the young chick decreased hepatic glycogen accumulation significantly.

Thyroid Hormones in Alcoholic Liver Disease

The relationship between alcoholic liver disease and circulating thyroid hormones was investigated in 124 hospitalized patients treated with placebo or propylthiouracil (PTU) for a maximum of 46 days in a double-blind study. Serum triiodothyronine (T3) levels on admission were significantly (P less than 10(-6) and inversely correlated with the severity of alcoholic liver disease. After hospitalization, changes in T3-levels in patients with low admission T3 significantly correlated (P less than 0.001) with the degree of spontaneous improvement of liver function (placebo group). Treatment with 300 mg of PTU daily (Orrego et al. Gastroenterology 76:105--115, 1979) markedly increased the rate of improvement in severely ill patients with low T3 on admission. In this group, serum T3-levels were also increased after PTU, but this increase did not correlate with the change in the patient's condition. It is suggested that the known inhibitory effect of PTU on peripheral deiodination of T4 to T3 is marked by a more marked improvement in liver function in this group. PTU treatment in this group reduced the free T4-index and increased TSH levels markedly (16%; P less than 0.02) toward levels found in hypothyroidism. PTU did not improve the condition of mildly ill patients with normal admission T3-levels, nor did it alter free T4-index or serum TSH levels in these patients. Serum T3-levels provide a sensitive indicator of the severity of alcoholic liver disease and of its response to conventional treatment. Serum T3-levels also distinguish between a group of patients, in whom low-dose PTU administration results in a beneficial effect, and another group, in whom no therapeutic effect of PTU is observed.

Effects of propylthiouracil and methylmercaptoimidazol on metabolism of thyroid hormones by cultured monkey hepatocarcinoma cells.

Monkey hepatocarcinoma cell monolayer cultures (NCLP-6E) metabolized thyroxine, 3,5,3'-triiodothyronine, 3,3',5'-triiodothyronine and 3,3'-diiodothyronine by phenolic and nonphenolic ring deiodinations and sulfation of the deiodinated products, as shown in previous work with this system. The effects of the antithyroid drugs, propylthiouracil (PTU) and methylmercaptoimidazole (MMI), on these processes was investigated. PTU, at 0.1 and 1 mM, inhibited only phenolic ring deiodination. MMI at 1 mM had no effect, but 32 mM inhibited deiodination of both rings as well as sulfation. The findings suggest that the increased serum rT3 level caused by PTU in vivo is the result of decreased rT3 deiodination, in contrast to the increased rT3 production which is caused by starvation.

Effect of Short-Term Therapy with Propylthiouracil in Patients with Alcoholic Liver Disease

The effect of propylthiouracil (PTU; 300 mg/day) on alcoholic liver disease was evaluated in 133 patients in a short-term randomized double-blind trial. Severity of the disease was assessed by a composite clinical and laboratory index (CCLI). A normalization rate (NR) representing the rate of improvement in CCLI was calculated. Patients with alcoholic hepatitis, with and without cirrhosis, showed a significantly higher NR on PTU (43.6 +/- 4.6) than on placebo (19.8 +/- 3.3; P less than 0.001). A similar effect was observed in patients with abnormal prothrombin (no biopsy): NR was 32.9 +/- 6.9 on PTU and 2.6 +/- 3.7 on placebo (P less than 0.005). The effect of PTU on each clinical and laboratory component of the CCLI was also compared in these two groups. In 38 patients with alcoholic hepatitis and in 25 with abnormal prothrombin, those on PTU showed a greater improvement in 15 of 15 items (P less than 0.001) and 14 of 15 (P less than 0.01), respectively. When patients were divided according to the severity of the disease into those in the lower and upper halves of the CCLI range (81 and 52 patients, respectively), PTU was shown to have a significant effect only in the latter: The NR was 41.4 +/- 3.8 on PTU and 22.5 +/- 4.2 on placebo (P less than 0.005). PTU was ineffective in patients with inactive cirrhosis.

Effect of propylthiouracil and thyroxine on the inactivation of somatostatin by rat hypothalamus

The inactivation of somatostatin by hypothalamic and brain extracts were studied in rats treated with propylthiouracil (PTU) alone or with PTU and thyroxine. 90 days after the onset of treatment with PTU, the potency of hypothalamic extract to inactivate somatostatin was increased almost 2-fold; while no change was observed for brain extract. Thyroxine reversed the enhancing effect of PTU on the activity of the enzyme(s) degrading somatostatin. A pH study shows that both brain and hypothalamic enzymic systems are different. These data suggest that the inactivation process of somatostatin by hypothalamic extract could be an important factor in the regulation of the hypothalamic-hypophyseal thyroid axis in rat.

Protective effect of propylthiouracil — Induced hypothyroidism against acetaminophen toxicity in the rat

Protective effect of propylthiouracil — Induced hypothyroidism against acetaminophen toxicity in the rat

The effect of altered thyroid state on prolactin binding to liver and 7,12-dimethylbenz(a)anthracene-induced mammary tumors in rats.

SummaryThe effects of propylthiouracil (PTU) and pharmacological doses of thyroxine (T4) on growth and prolactin (PRL)-binding activity of DMBA-induced mammary tumors were studied. The hypo- or hyperthyroidism induced by these respective treatments did not affect the growth rate of established tumors, PRL binding activity in these tumors or plasma PRL in the tumor-bearing rats. In contrast, both PTU and T4 treatments caused a large reduction of PRL binding activity in the liver.

Effects of propylthiouracil, actinomycin D and cycloheximide on the aminotransaminase activity in the thyroid gland of rat

Effects of propylthiouracil, actinomycin D and cycloheximide on the aminotransaminase activity in the thyroid gland of rat

Effect of propylthiouracil on intestinal tumor formation by azoxymethane in rats.

Treatment with propylthiouracil (PTU) resulted in a significant decrease in azoxymethane-induced intestinal tumors, total concentration of fecal bile acids as well as the fecal neutral steroids, cholesterol and coprostanol. Thus, a hypothyroid state induced by PTU treatment may affect intestinal carcinogenesis in this animal model by lowering the concentration of fecal bile acids and neutral steroids.

Thyroid Hormone Regulation of Extrathyroidal Iodoproteins

The effect of thyroid status on plasma and tissue levels of labeled nonextractable iodine (NEI) derived from the metabolism of radioiodothyronines was examined in the rat. Concentrations of radioiodoprotein were substantially elevated in plasma, kidney, and liver in thyroidectomized animals 72 h postinjection of [125I]triiodothytonine ([125I]T3). Similarly, total rat concentrations of radioactive NEI were increased (52%) 72 h after injection of [125I]T3. NE125I concentrations from [125I]T3 in plasma, kidney, and liver were diminished progressively in thyroidectomized animals maintained on increasing doses of thyroxine replacement, demonstrating that iodoprotein levels were inversely related to thyroid state. The plasma disappearance rate of radioiodoprotein from [125I]T3 was markedly slowed in hypothyroid animals and accelerated in intact controls rendered hyperthyroid with daily injections of T4, 8 mug/100 g BW. Propylthiouracil (PTU) treatment of thyroidectomized rats maintained on T4, 2 mug/100 g BW per day resulted in increased NE125I from [125E]T3 in plasma, kidney, and liver. The results of the foregoing investigations suggest that thyroid hormone regulates levels of iodothyronine-derived iodoproteins by influencing the rate of degradation of iodoproteins. Moreover, the observed elevation of iodoprotein levels in T4-maintained thyroidectomized animals after PTU administration appears consistent with the modification of thyroid status due to the peripheral antithyroxine effect of PTU.

Stimulation by propylthiouracil of the hexose monophosphate shunt in human polymorphonuclear leucocytes during phagocytosis.

The effect of propylthiouracil on glucose metabolism in human polymorphonuclear leucocytes was studied. At a therapeutically achievable concentration (0.1 mM), propylthiouracil stimulated hexose monophosphate shunt activity in normal leucocytes during phagocytosis but not in resting cells. However, in the presence of hydrogen peroxide it stimulated hexose monophosphate shunt activity in resting cells, and in the soluble fraction when reduced glutathione and reduced nictotinamide adenine dinucleotide phosphate (NADPH) were also present. Propylthiouracil had nor effect on glucose-1-C oxidation in either phagocytosing or resting leucocytes obtained from two male patients with chronic granulomatous disease. Stimulation of the hexose monophosphate shunt activity in normal leucocytes during phagocytosis also was demonstrated with methimazole, thiouracil and thiourea, but not with adenine, uracil or urea. There was an apparent minimal common structure requirement in thriourea. Propylthiouracil had no effect on phagocytosis, formate oxidation, glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase or catalase activities. Thus, the stimulation of the hexose monophosphate shunt activity by propylthiouracil is dependent on hydrogen peroxide and is best explained by its stimulation or participation in the glutathione cycle.

The effects of hypothyroidism and 2,4-dinitrophenol on growth hormone synthesis.

After the administration of several agents which alter thyroid function, storage and synthesis of growth hormone (rGH) and storage of prolactin (rPRL) were studied in the rat pituitary gland. Hormone concentrations in pituitaries were measured by gel electrophoresis; synthesis was measured in pituitary glands incubated in vitro. The pituitary concentration of cyclic adenosine 3′,5′-monophosphate (cyclic AMP) and pituitary adenylate cyclase activity were also determined. In addition, serum thyroxin concentrations and binding of DL-thyroxin-2-14C by pituitary and hypothalamic tissues were measured. We obtained the following results. Hypothyroidism produced by propylthiouracil (PTU) reduced the synthesis of rGH 90-97% and that of rPRL 70-78% and resulted in a fall of 80% in pituitary concentrations of rGH and rPRL. These effects of PTU were reversed by the administration of thyroxin. Dinitrophenol (DNP) reduced serum thyroxin 25% and the concentrations of rGH and rPRL in the pituitary as well as their rates ...

Hypothalamo-hypophysial relations in amphibian larvae

The results of studies on the differentiation of the preoptic nucleus and of experiments regarding the effects of propylthiouracil and extirpation of the preoptic area demonstrate that in Xenopus laevis tadpoles a thyrotropin-releasing factor (TRF) is formed in peptidergic cells in the dorsal part of the preoptic nucleus. The differentiation of this nucleus depends on thyroid hormones, but at the same time these hormones inhibit the activity of the TRF cells. Young larvae of X. laevis acquire the ability to adapt themselves to a white background simultaneously with the appearance of aminergic neurosecretory centers in the caudal hypothalamus. During prometamorphosis these centers comprise a paraventricular organ (PVO), a nucleus infundibularis, fiber tracts to the telencephalon and to the pars intermedia of the adenohypophysis, and a nucleus in the caudalmost part of the dorsal tuber cinereum. The PVO consists of sensory nerve cells and cells secreting products into the cerebrospinal fluid; the infundibular nucleus contains numerous liquor-contacting neurons. The aminergic neurosecretory cells contain catecholamines such as dopamine. Depletion of these cells by reserpine leads to a dispersion of melanin granules in the skin melanophores. It is believed that among the functions of the aminergic neurosecretory centers is the production of a melanotropin-inhibiting factor. In the ventral tuber cinereum of X. laevis, neurosecretory cells are situated that are neither peptidergic nor aminergic. They are more active in adult animals than in tadpoles.

Effects of propylthiouracil on liver morphology in DDT-treated rats

Rats receiving 100 ppm, p,p′-DDT in their drinking water for a period of 45 days show reduced basophilia of the centrilobular liver cells. The basophilic fragments are scattered throughout the cytoplasm in most of these cells. The animals receiving 100 ppm PTU in their drinking water show similar morphological changes. The animals receiving p,p′-DDT plus PTU exhibit advanced changes involving almost all the cells of the inner two-thirds of the hepatic lobule. The ergastoplasm is reduced to a few small fragments located near the cell membrane. The remainder of the cytoplasm is very clear and foamy in appearance. It is considered that the changes in the liver induced by p,p′-DDT are potentiated by the effect of PTU on the hypophyso-thyroid system. This view is supported by our previous findings in the liver of surgically thyroidectomized p,p′DDT-receiving rats.

The influence of estrogen on sterol synthesis in hypothyroid rats

The interaction of hypothyroidism and estrogen administration on cholesterol metabolism was studied. Propylthiouracil (PTU) was administered in the drink for 3 weeks and estradiol benzoate in corn oil was injected subcutaneously every second day during the last two weeks. Four-hour incorporation of 14C-acetate into hepatic and serum digitonin-precipitable sterols was decreased by 50% in hypothyroid animals. Whereas 10 ug. of estradiol benzoate had no influence on cholesterol metabolism in euthyroid rats, the effect of PTU was completely reversed by concomitant estrogen. It is suggested that in the absence of thyroid hormone, estrogen may influence particular steps in the cholesterol metabolic sequence in such a way as to effect a net augmentation of sterol synthesis.

Antithyroid effects of 3-amino-1,2,4-triazole.

SummaryThe effects of 3-amino-1,2,-4-triazole (ATZ) on weight, content of iodine, and histology of the thyroid in rats were determined and compared to the effects of propylthiouracil (PTU), and KCIO4. In an 83-day period of treatment, ATZ and PTU produced goiters of comparable size. The KCIO4 treatment resulted in slightly greater depletion of iodine in the thyroid, smaller goiters, and less thyroxine depletion of the thyroid. The effect of ATZ treatment on intrathyroid metabolism of iodine in rats was studied and compared to similar studies in rats without treatment. In the ATZ-treated group, there was a progressive decrease in T3 and T4 and a slight increase in the proportion of MIT. The biologic half-life of 131I in the thyroid of the control and treated groups was 4.9 and 1.3 days, respectively. These findings are similar to those found previously for PTU and show that ATZ, like PTU, not only interferes with organification of iodine but also inhibits the coupling of iodotyrosines to form iodothyronines.