Effects Of Propylthiouracil Research Articles

Differential effect of propylthiouracil on in vitro iodoamino acid synthesis by thyroid lobes from intact or hypophysectomized rats.

Thyroid lobes from intact and hypophysectomized rats fed an iodine-deficient or high-iodine diet were incubated with carrierfree 131I- in graded concentrations of PTU. In the lobes from intact rats there was a negative correlation of the DIT/MIT ratio with concentration of PTU, confirming many previous in vivo and in vitro studies. In contrast, in the lobes from hypophysectomized rats there was no significant correlation of DIT/MIT ratio with PTU concentration. These observations are similar tothose made previously in vivo and establish that the qualitative difference in the effect of PTU on the DIT/MIT ratio in intact compared to hypophysectomized rats is not due to a difference in the extrathyroidal metabolism of PTU in these 2 types of animals. It is suggested that this differential effect of PTU might be due to some alteration in the structure of thyroid protein produced by hypophysectomy. (Endocrinology 83: 592, 1968)

The effects of propylthiouracil, thyroxine, and hypophysectomy on the iodinating activity of the rat thyroid gland.

The effects of increasing or decreasing the endogenous secretion of thyroid-stimulating hormone on the iodinating activity of the rat thyroid gland were investigated. The thyroid iodinating activity of rats on 0.01% propylthiouracil in the drinking water increased linearly for 3 days and reached a maximum of 230 to 240% of the control on or about the fourth day of treatment. The daily injection of thyroxine (10 μg/100 g intraperitoneally) or hypophysectomy resulted in a rapid decrease in the iodinating activity between the first and second day, approaching a basal level by the third day. When the iodinating activity was suppressed for 4 days by daily injections of thyroxine, the activity began to rise on the fifth day after termination of thyroxine treatment.

Hypothalamic neurosecretion and metamorphosis in Xenopus laevis. I. The effect of propylthiouracil.

Normal and propylthiouracil (PTU) treated Xenopus laevis tadpoles were fixed during all stages of metamorphosis and sagittal sections were stained with aldehyde fuchsin (AF) or pseudoisocyanine (PIC). Whereas AF positive neurosecretory material could only be demonstrated in the preoptic nucleus from late prometamorphosis, increasing amounts of PIC positive material were found in cells of the dorsal part of the preoptic region from early premetamorphosis. The development of these cells correlated with that of the thyrotropic cells and the thyroids. Likewise, signs of hyperactivity in thyroids and thyrotropic cells of PTU treated larvae were accompanied by a depletion of the dorsal PIC positive cells. In the ventral preoptic region PIC positive cells developed from late prometamorphosis in control larvae, but failed to do so in PTU treated animals. It is argued that the differentiation of the PIC positive cells is largely dependent on thyroid hormones; that the dorsal PIC positive cells may produce a thyrotropin releasing factor; and that the function of these dorsal cells is inhibited by thyroid hormones.

Effect of propylthiouracil and methimazole on the oxygen comsumption of hypothyroid rats receiving thyroxine or triiodothyronine.

The calorigenic response to thyroxine and triiodothyronine has been compared in hypothyroid rats treated with either propylthiouracil or methimazole. Propylthiouracil reduced the calorigenic response to thyroxine, but methimazole did not. Neither methimazole nor propylthiouracil diminished the calorigenic response to triiodothyronine, and methimazole may even have increased this response when 80μg/day of triiodothyronine was administered. When methimazole was replaced by propylthiouracil in the diet of rats treated with thyroxine, the oxygen consumption fell slowly over a period of 2 weeks, but there was little rise in oxygen consumption during the 2 weeks after the diet was changed from propylthiouracil to methimazole. (Endocrinology 81: 1018, 1967)

Effect of propylthiouracil and I-131 on blood pressures of thyrotoxic patients.

Effect of propylthiouracil and I-131 on blood pressures of thyrotoxic patients.

Effect of propylthiouracil on preference threshold of rats for NaCl solutions.

SummaryChronic administration of the antithyroid drug, propylthiouracil (PTU) reduced the NaCl preference threshold of rats from one-fifth to one-eighth that of untreated controls. Preference threshold of normal rats lay between .02 and .05 M while threshold of PTU-treated rats lay between .003 and .01 M. Differences between thresholds were significant. The reduction in preference threshold for NaCl solution adds further to the striking similarities of PTU-treated and adrenalectomized rats.

Effects of propylthiouracil and thyroid feeding on the response of mice to injected convulsant barbiturate.

IN 1961, Carrier and Buday1 enumerated the substances the toxicity of which is increased in hyperthyroid animals. Among these was hexobarbital2. Prange et al.7 showed that mice fed desiccated thyroid slept longer than controls after injection of pentobarbital, while mice fed propyl-thiouracil (PTU) slept less.

EFFECT OF THYROXINE ON INTAKE AND LOSS OF SODIUM BY PROPYLTHIOURACIL-TREATED RATS.

Administration of thyroxine to propylthiouracil (PTU) -treated rats returned to control level both their excessive spontaneous intake of NaCl solution and their excessive losses of sodium and water following intraperitoneal loading with isotonic saline. Since these changes occurred in the presence of PTU, it can be assumed that the effects of PTU on sodium intake and loss are due to lack of thyroxine and not to extrathyroidal effects of PTU. It was also observed that administration of thyroid powder in the sodium-deficient diet of normal rats decreased spontaneous intake of NaCl solution below the level of controls. The results suggest that both intake and loss of sodium are influenced by the functional activity of the thyroid gland. (Endocrinology 75: 27, 1964)

IMMUNOLOGIC INHIBITION OF ENDOGENOUS OR EXOGENOUS THYROTROPIN IN VARIOUS SPECIES.

SummaryA modification of the Querido bio-assay for thyrotropin is presented along with log dose-response curves for USP Reference Standard Thyrotropin in 2 different strains of mice. The immimobiologic effects of antisera to bovine thyrotropin (TSH) on either endogenous or exogenous TSH were determined in guinea pigs, intact or hypophysectomized rats and mice. In thyroxinized guinea pigs and thyroxinized intact or hypophysectomized rats, passively administered rabbit antiserum to bovine TSH neutralized the biologic activity of exogenous bovine TSH. Rabbit antiserum passively administered to guinea pigs, rats or mice inhibited the effects of propylthiouracil (PTU) on goitrogenesis and on radioactive iodine uptake, indicating biologic neutralization of endogenous TSH in these species. These findings suggest a molecular similarity of guinea pig, rat and mouse thyrotropin.

Effect of propylthiouracil upon thyroidal I-131 release in the methimazole-thyroxine treated rat.

Propylthiouracil (PTU) in doses of 0.05, .15, 1 or 10 mg/day quickly accelerated the rate of thyroidal I131 release in 15 of 21 adult rats whose recycling of I131 was prevented by methimazole and whose initial thyroidal I131 release was slowed by exogenous thyroxine. The magnitude of the response was independent of PTU dose. One or 2 rats failed to respond to each dose of PTU administered. Rats whose thyroidal I131 release rates were accelerated by PTU had significantly higher plasma levels of radioactivity than rats whose thyroidal I131 release slopes were unaffected by PTU. The percentages of protein-bound I131 and inorganic I131 in the plasma, however, were unchanged. These data confirm the thesis that PTU administration promptly causes an increased thyrotrophin secretion by the pituitary.

AGE FACTOR IN THE RESPONSE OF MICE TO THE ADMINISTRATION OF RADIOACTIVE IODINE (I-131) AND PROPYLTHIOURACIL (PTU).

Mice (C57BL strain) made hypothyroid by injection of 400 mu C /sup 131/ I developed articular changes which were termed athyroid joirt disease. These lesions were more readily produced in growing than in young adult animals. Similar joirt disease was also observed after feeding propylthiouracil (PTU) to growing mice. Attempts were made to determine whether or not old age modified these effects of thyroid deficiency. The lower incidence of athyroid joint disease in mice of the DBA strain receiving /sup 131/I in late adulthood than that seen in mice treated correspondingly during the growth period was noted regardless of whether age at death or post-treatment survival time were used for reference. The difference in the incidence of joint disease in mice given /sup 131/I in early or late adulthood, respectively, might be attributed to an age factor as well as to the difference in the post-treatment interval. PTU appeared to be less effective in producing articular lesions than injection of /sup 131/I, and no age factor could be demonstrated in the articular effects of PTU under the conditions studied. The evolution of spontaneous osteoarthrosis was not affected by treatment with either /sup 131/I or PTU during late adulthood. In themore » hypophysis the occurrence of thyroidectomy cells subsequent to treatment with / sup 131/I or PTU is in accordance with flndings obtained previously in C57 mice. In mice receiving /sup 131/I at the age of one year, microscopic nodules form and this coincides with the high incidence of hypophyseal tumors observed in C57 mice given /sup 131/I at 6 months of age. This strain difference in the reaction of the arterior hypophysis might be secondary to strain differences in thyroid activity. The active thyroids of C57 mice might bind less of the isotope and permit a larger amount of it to reach the hypophysis; there the isotope might exert a tumorigenic effect on the thyrotroph cells which are already stimulated by the absence of thyroid hormone. (BBB)« less

Influence of Thiourea, Potassium Perchlorate and Thiocyanate and of Graded Doses of Propylthiouracil on Thyroid Hormone Metabolism in Thyroidectomized Rats, Isotopically Equilibrated with Varying Doses of Exogenous Hormone

Daily doses of propylthiouracil (PTU) as low as 50 μg per rat result in a depression of the peripheral deiodination of Lthyroxine in thyroidectomized animals isotopically equilibrated with I131-labeled L-thyroxine. Administration of PTU is accompanied by similar alterations of the peripheral metabolism of triiodo-L-thyronine in thyroidectomized rats maintained with the latter hormone. Maximal extrathyroidal effects of PTU on the metabolism and effectiveness of L-thyroxine are obtained with doses of 500 ng per rat or higher. The influence of a given dose of PTU was studied in groups of thyroidectomized rats which were equilibrated isotopically with varying doses of L-thyroxine ranging from 0.5 to 50 μg per rat per day, and it was observed that the drug depressed thyroxine deiodination to a rather constant proportion of the available hormone. Therefore the effects of PTU on the actual amount deiodinated peripherally may be overcome by adequately increasing the hormonal supply. Thiourea, potassium thiocyanat...

Effects of propylthiouracil and thiouracil on the metabolism of thyroxine and several of its derivatives by rat kidney slices in vitro.

The metabolism of thyroxine (T4), 3,5,3′-L-triiodothyronine (T3), tetraiodothyroacetic acid (TA4) and triiodothyroacetic acid (TA3) by rat kidney slices in vitro has been studied to determine the effects of thiouracil (TU) added in vitro and of propylthiouracil (PTU) administered in vivo. These agents decreased the deiodination of T4 and increased the generation of conjugates, without altering the tissue oxygen consumption. Perchlorate and methimazole, comparably administered, were without effect. TU and PTU induced alterations in the metabolism of TA4 and T3 similar to those which occurred in the case of T4. However, the effects were less consistent with T3 than with T4. The results obtained with TA3 were highly variable, significant alterations of in vitro metabolism being obtained in less than half the experiments. In separate experiments, the prevention of PTU-induced goiters by varying doses of T4 was studied in order to correlate the effects upon tissue QO2, T4 deiodination and serum PBI. In confirm...

Comparison of the Effects of Propylthiouracil and Sulfadiazine on Thyroidal Biosynthesis and the Manner in Which They Are Influenced by Supplemental Iodide1

Sulfadiazine (SD) and propylthiouracil (PTU) were administered to rats parenterally or in the diet for varying periods of time and over a wide dosage range. The effects of these drugs on thyroid weight and biosynthetic processes were compared. Both were qualitatively similar in their antithyroid activity. Coupling of iodinated tyrosines to form iodothyronines was most readily inhibited, then iodination of monoiodotyrosine, while iodination of tyrosine was much more resistant to inhibition. Supplementary iodide decreased the goiter produced by PTU but not that produced by SD. Iodide did not alter the effect of PTU on thyroidal biosynthesis but increased that of SD at least 1,000-fold. A marked potentiation of the inhibitory effect of SD was produced by as little as 10 ng KI daily, while a complete inhibition of all organic binding of iodine was produced with SD plus 100 jug KI daily. Iodide maximally potentiated the inhibitory effect of SD within 24 hours. No definite inhibition of thyroidal biosynthesis w...

Studies on the production of high radioiodine uptake goiter with propylthiouracil.

Rats were fed a low iodine diet with propylthiouracil added at a level of from 2×1O−5 to 15×lO−2%. In 2 of the 3 experiments, half the animals received supplementary iodine. In no instance was the thyroid enlargement in propylthiouracil-fed rats significantly greater than that of the respective controls without a concomitant lowering of radioiodine uptake. Iodine supplementation favored the formation of diiodotyrosine and T4 over monoiodotyrosine and T3. Propylthiouracil inhibited formation of diiodotyrosine and T4 to a greater extent than it did monoiodotyrosine and T3. Supplementary iodine decreased goitrogenesis but increased the inhibitory effects of propylthiouracil on radioiodine uptake and on formation of diiodotyrosine and T4.

Effect of propylthiouracil and thyroid-stimulating hormone on glucose oxidation in rat thyroid tissue.

Previous observations that small amounts of propylthiouracil increased the uptake of radioiodine and the consumption of oxygen by rat thyroid slices led to study of the effect of propylthiouracil on the metabolism of C14 labeled glucose. A high concentration of propylthiouracil (10−3M) in the medium diminished the production of C14O2 by rat thyroid slices, at 1 hour, from both glucose-1-C14 and glucose-6-C14. However, with small doses of propylthiouracil (10−8M), the production of C14O2 from glucose- 6-C14 was markedly stimulated (10-fold; P<0.001) whereas the production of C14O2 from glucose-1-C14 was still inhibited (P<0.001). Thyrotropin stimulated the oxidation of glucose-1-C14 to C14O2 but had no significant effect on the production of C14O2 derived from glucose-6-C14. The results suggest that small amounts of propylthiouracil stimulate the production of C14O2 from glucose-6- C14 by modifying the various pathways of carbohydrate metabolism in rat thyroid slices (possibly by a stimulation of the Embde...

The effect of propylthiouracil on exocrine glands.

This study was designed to compare the effect of hypothyroidism on the submaxillary gland with that on other exocrine glands. Weights and enzymatic activity of submaxillary gland, parotid gland and pancreas were determined at 30, 60 and 90 day intervals in a control group of rats fed ad libitum, an experimental group fed ad libitum and receiving .075% propylthiouracil in their drinking water, and a pair-fed group. Rats on propylthiouracil reduced their food intake by about 23-30%. The pair-fed group showed that this degree of restriction of food intake: 1) resulted in an increase in the relative weights of the submaxillary gland and of the pancreas, 2) caused a significant decrease in the specific protease activity of the submaxillary gland, but did not affect the specific protease activity of the pancreas, and 3) had no effect on the specific amylase activity of the pancreas or parotid. After discounting these effects of reduced food intake in the experimental animals, it was concluded that propylthioura...

Interference with deiodination of some thyroxine analogues in the rat.

Triiodothyronine, its propionic acid analogue and D-thyroxine are rapidly deiodinatod l)y the rat. Propylthiouracil greatly reduced the rate of deiodination of these compounds and resulted in higher concentrations of PBI than were found in control animals whose thyroids were blocked by potassium perchlorate. The effectiveness of the thyronine derivatives to prevent goiter was influenced by an extrathyroidal effect of propylthiouracil.

The Effect of Propylthiouracil on the Intrathyroid Metabolism of Iodine in Rats

It has long been known that treatment with propylthiouracil and other antithyroid drugs inhibits organic binding of iodine and leads to a reduction in total iodine in the thyroid (1). The work of Franklin et al. (2-4) showed that these agents also prevent incorporation of radioiodine into organic compounds by thyroid slices in Z.&O. Pitt-Rivers (5), finding that acetyldiiodotyrosine did not form acetylthyroxine when incubated with these compounds, suggested that they may act by inhibiting coupling of diiodotyrosines to form thyroxine in vivo. However, Slingerland (6) was unable to obtain evidence in support of this possibility. Recent investigations have suggested that although propylthiouracil blocks the iodination of tyrosyl groups in thyroglobulin, it inhibits the formation of diiodotyrosine more strongly than the formation of monoiodotyrosine. Slingerland et al. (7) felt that this block favored the synthesis of triiodothyronine over that of thyroxine, whereas Richards and Ingbar (8) found no triiodothyronine and a reduced quantity of thyroxine in the glands of rats treated with small amounts of propylthiouracil. All of the studies on the effect of propylthiouracil on the intrathyroid metabolism of radioiodine have been conducted by administration of radioiodine after treatment with graded doses of the drug. In the studies to be described we thought it might be informative to “label” the thyroids of animals before drug treatment and to follow subsequently the radioactivity in the several iodine-containing compounds in the glands after instituting antithyroid treatment.

The effects of propylthiouracil and perchlorate on the biogenesis of thyroid hormone.

Graded doses of propylthiouracil (PTU), administered to rats 30 minutes prior to tracer doses of I131 and 270 minutes prior to sacrifice, resulted in progressive reductions in total I131 uptake, I131 organic-uptake, and alterations in the relative proportions of the radioiodinated amino acids. Progressive blockade was associated with an increasing proportion of MIT, and a decreasing proportion of DIT and total thyronines. Comparable reductions in thyroidal I131 organic-uptake induced by perchlorate were not attended by alterations in relative composition of the radioiodinated amino acids. Administration of PTU to rats previously treated with TSH resulted in alterations in radioiodinated amino acid composition similar to those observed with PTU alone, despite a normal I131 organic-uptake. The effects of PTU cannot therefore be ascribed to the reduction in the flux of iodine into organic moieties. Triiodothyronine was detected in less than half of the glands from treatment-free controls and in none of the g...