Showing papers on "Propylthiouracil published in 1978"

The Influence of Fasting, Diabetes, and Several Pharmacological Agents on the Pathways of Thyroxine Metabolism in Rat Liver

Abstract: As judged from both paper and column chromatography, slices or homogenates of liver from rats fasted for 48 h displayed a lesser rate of generation of (125)I-labeled 3,5,3'-triiodothyronine (T(3)) from (125)I-labeled thyroxine (T(4)) added to incubation media than did preparations from normal chow-fed animals. A similar defect in the conversion of T(4) to T(3) in the livers of fasted animals was observed when preparations were incubated with substrate concentrations of T(4) so that T(3) generation could be assessed by radioimmunoassay. The effect of fasting could be prevented, wholly or in part, by administration of glucose in the drinking water to otherwise fasted animals, and the degree of prevention appeared to be proportional to the concentration of glucose employed. Diminished generation of T(3) from T(4) was similarly evident in the livers of animals with streptozotocin-induced diabetes mellitus, and this defect was overcome by the provision of insulin in vivo, but not in vitro. Decreased formation of T(3) from T(4) was also observed in preparations of liver from animals given dexamethasone, amiodarone, and propylthiouracil. In no case could these effects on the net formation of T(3) from T(4) be explained by effects of the experimental conditions on the degradation of the T(3) generated, as judged from the rate of degradation of exogenous (125)I-T(3) measured in parallel incubates. An analysis of the rate of disappearance of (125)I-T(4) from reaction mixtures in relation to the rate of appearance of (125)I-T(3) and (125)I-iodide was employed to estimate the activity of the 5-monodeiodinating pathway of T(4) metabolism that leads to the formation of 3,3',5'-triiodothyronine (reverse T(3)). Such estimates indicated that reverse T(3) formation was actively proceeding in the preparations studied, was slightly enhanced by fasting, was unaffected by dexamethasone and amiodarone, and was markedly inhibited by propylthiouracil. In view of the similarities between the effect of these experimental manipulations on the generation of T(3) from T(4) by rat liver in vitro to their effects on the production rates and serum concentrations of T(3) in man, it is concluded that the rat liver system provides a suitable model for the study of factors that influence the conversion of T(4) to T(3) in man. In addition, the findings strongly indicate that this process, at least in the liver, is closely linked to the utilization of carbohydrate.

Thyroxine 5′-Deiodinase Activity of Rat Kidney: Observations on Activation by Thiols and Inhibition by Propylthiouracil

Abstract: Enzymatic 5′-deiodination of T4 in various tissues is known to be stimulated by thiols and inhibited by propylthiouracil (PTU). Dithiothreitol (DTT) stimulation of rat kidney T4 5′-deiodinase followed saturation kinetics. Inhibition of the enzyme by PTU (10-5 M) was overcome in a concentration-dependent manner by DTT, methimazole (MMI), and thiourea. Pretreatment of catalytically active kidney microsomal preparations with PTU caused persistent inhibition of enzyme activity, assayed in the absence of PTU. Similarly, injection of PTU in rats in a dosage of 5 μg/100 g BW or greater significantly impaired T4 5′-deiodination in subsequently isolated kidney microsomal preparations. Reagents that cleave disulfide bonds (DTT and KCN), as well as the reductant, Na2S2O4, and the thioureylene, MMI, partially restored activity to PTU-inactivated enzyme in a time- and concentration-dependent way. These observations suggest that PTU inhibition of T4 5′-deiodinase results from an interaction of PTU with the enzyme, poss...

The irreversible inactivation of thyroid peroxidase by methylmercaptoimidazole, thiouracil, and propylthiouracil in vitro and its relationship to in vivo findings.

Abstract: A reinvestigation of the mechanism of action of methylmercaptoimidazole, propylthiouracil, and thiouracil on thyroid peroxidase (TPO) was undertaken. A preliminary incubation of TPO and H2O2 with methylmercaptoimidazole, propylthiouracil, or thiouracil was carried out in the absence of oxidizable substrates (i.e. I- or guaiacol). This incubation resulted in irreversible inactivation of TPO. The extent of inactivation could be determined after removal of the drug by gel filtration or by dilution into the assay mixture. Preincubation, as above, in the presence of iodide or thiocyanate prevented the irreversible inactivation of TPO. Rats receiving doses of these drugs which completely inhibited protein-bound iodine formation showed normal levels of TPO in their thyroid glands 30 min after drug administration. These findings suggest that the initial in vivo action of these drugs is to block iodination by trapping oxidized iodide, not by acting as "general inhibitors" of the TPO.

Mechanism of Action of Thioureylene Antithyroid Drugs: Factors Affecting Intrathyroidal Metabolism of Propylthiouracil and Methimazole in Rats*

Abstract: Experiments were performed with rats to test the physiological significance of a previously proposed mechanism of action of thioureylene antithyroid drugs, which had been derived from results obtained with a model system containing purified thyroid peroxidase. Two features of the previously proposed scheme were tested: 1) the effects of drug dosage and 2) the effects of iodine deficiency. In the dosage experiments, rats were injected with graded doses of [35S]PTU (0.18–59 μmol) or [35S]MMI (0.16–18 nmol). Thyroid glands were removed 1 and 6–8 h later and 35S distribution in the homogenates was determined by paper chromatography. Serum samples were also analyzed by the same procedure. From the measured 35S activity in the various components and from the known specific activity of the injected drugs, it was possible to calculate thyroidal concentrations of unchanged drug and drug metabolites. At low doses, thyroidal concentrations of unchanged 6-propyl-2-thiouracil (PTU) and 1-methyl-2-mercaptoimidazole (MM...

Evidence that control of fetal thyrotropin secretion is independent of both the fetal and maternal hypothalamus.

Abstract: Propylthiouracil (PTU) administered to pregnant rats from day 18–21 of gestation caused a significant increase in maternal and fetal thyroid weight and plasma TSH. Fetal encephalectomy on day 18 did not significantly affect basal or PTU-stimulated pituitary- thyroid function. Destruction of the basal hypothalamus in the mother on day 13 or 16 markedly reduced maternal plasma TSH and thyroxine and prevented a PTU-induced increase in thyroid size, but did not affect fetal pituitary-thyroid function. Plasma PRL was undetectable in both intact and encephalectomized fetuses at 21 days but was increased > 6-fold to approximately 2 μg/ml in the mothers by maternal hypothalamic destruction. We conclude that fetal pituitary-thyroid function in the rat is not dependent on either fetal or maternal hypothalamic TRH. (Endocrinology 102: 852, 1978)

Metabolism of Thyroid Hormones by Rat Thyroid Tissue in Vitro

Abstract: Rat thyroid lobes or hemilobes have been incubated in Krebs-Ringer phosphate buffer containing labeled T4 and/or T3, and the products were separated by paper chromatography. Labeled T4 was actively degraded; about half of the T4 metabolized was recovered as T3. Labeled T3 was also metabolized, but less rapidly than T4. Other than T3 produced from T4, the major products from both hormones were inorganic iodide and iodoprotein; the latter was presumably a secondary product of iodide organification because its formation was inhibited by hypoxia and methimazole. Feeding the animals a low iodine diet increased their hormone-metabolizing activity. Incubation under nitrogen did not affect the rate of T4 degradation, but partially inhibited T3 degradation. Degradation of both hormones was unchanged in the presence of methimazole and ascorbate, was markedly inhibited by 1 mM propylthiouracil (PTU), and was partially inhibited by azide and cyanide. Thyroid tissues concentrated both hormones, tissue to medium gradie...

Prospective randomized comparison of propylthiouracil.

Abstract: Forty-nine patients with Graves' disease were randomly divided into two groups. One group received propylthiouracil, 150 mg every eight hours, and the other group received propylthiouracil, 450 mg as a single daily dose. All patients' conditions were evaluated clinically and chemically at two-week intervals. The response to the divided dosage schedule was prompt and predictable, and by ten weeks all but one patient had achieved remission. The group that received the single daily dose regimen responded less favorably, and at ten weeks ten patients had failed to achieve remission (P (JAMA239:2457-2459, 1978)

The effect of iodine deficiency and propylthiouracil on the hypothalamo--pituitary--thyroid axis in the neonatal rat.

Abstract: The effect of chronic propylthiouracil (PTU) and low iodide diet (LID) on the development of the hypothalamo–pituitary–thyroid axis in the rat has been studied. Pregnant and neonatal rats received ...

Selective Inhibition of the Secretion of Triiodothyronines from the Perfused Canine Thyroid by Propylthiouracil

Abstract: In order to assess a possible influence on the relative proportions of T4, T3, and rT3 in thyroid effluent, the thyroid-blocking agents, propylthiouracil (PTU) and methylmercaptoimidazol (MMI), were administered to perfused canine thyroids. The dog has two distinct thyroid lobes which were both perfused independently, one acting as a control for the other. T4, T3, and rT3 in thyroid effluents and thyroid hydrolysates were measured radioimmunologically. During control perfusion the T4:T3 and T4:rT3 ratios in thyroid effluent were considerably lower than in thyroid hydrolysates [t4:t3 (wt/wt), 6.1 +/- 2.0 vs. 12.8 +/- 4.4; T4:rT3, 23.0 +/- 5.9 vs. 69.7 +/- 29.1; mean +/- SD; n = 8; P less than 0.001], i.e. T3 and rT3 were secreted preferentially to T4. Infusion of PTU (1 mmol/liter) induced a gradual increase in both the T4:T3 and T4:rT3 ratios in thyroid effluent. The variation in the T4:rT3 ratio appeared somewhat earlier than that in the T4:T3 ratio. Both ratios eventually approached the ratios in thyroid hydrolysates. The change in ratios was caused by a PTU-induced decrease in the release of T3 and rT3 while the release of T4 was practically unaffected. In contradistinction, infusion of MMI did not affect the T4:T3 or T4:rT3 ratios in thyroid effluent. As PTU but not MMI inhibits T4 deiodination in peripheral tissues, the results of the present study suggest that part of the T3 and rT3 secreted from the thyroid stems from T4 deiodinated during the secretion by a mechanism similar to the T4-deiodinating processes in peripheral tissues.

The Formation of Tri-Iodothyronine and Reverse Triiodothyronine from Thyroxine in Isolated Rat Renal Tubules

Abstract: 1. Conversion of thyroxine into triiodothyronine and reverse tri-iodothyronine in intact cells was studied with isolated renal tubules prepared by collagenase digestion. 2. Conversion of thyroxine into triiodothyronine and reverse tri-iodothyronine increased progressively for at least 90 min. 3. Studies of tri-iodothyronine production from increasing amounts of thyroxine revealed that the thyroxine to tri-iodothyronine conversion is saturable. 4. Iodide and carbimazole had no effect on the thyroxine to tri-iodothyronine conversion. 5. 6-Propyl-2-thiouracil had a direct noncompetitive inhibitory effect on the conversion of thyroxine into tri-iodothyronine with a 75% inhibition of the conversion at a propylthiouracil concentration within the therapeutic range in vivo. Propylthiouracil also inhibited the net formation of reverse tri-iodothyronine from thyroxine at a similar propylthiouracil concentration, as well as inhibiting the subsequent degradation of reverse triiodothyronine.

Use of I-123 in Early Radioiodide Uptake and Its Suppression in Children and Adolescents with Hyperthyroidism

Abstract: Absolute activity measurement of I-123 by coincidence counting was used to study the early thyroidal iodide uptake in 20 hyperthyroid children. Patients were pretreated either with methimazole or propylthiouracil before injection of Na123I. The usual method of analysis of the early uptake was modified to account for a rapidly equilibrating compartment, to give thyroidal iodide trapping rate constant (K1) and absolute iodide uptake (AIU). The suppressibility of the early uptake by triiodothyronine (T3) was evaluated in some patients. The upper limit of normal for K1 was 0.03 min-1 and for AIU was 0.04 microgram/min. In the hyperthyroid subjects, K1 and AIU were in the hyperthyroid range before and after T3 suppression. For patients with suppressible uptake, remission from hyperthyroidism was maintained for 6 mo to 2 1/2 yr. Only two patients with nonsuppressible uptake achieved remission from hyperthyroidism, perhaps because of coexistence of thyroiditis.

Dietary subacute toxicity of ethylene thiourea in the laboratory rat.

Abstract: Ethylene thiourea (ETU) was fed to groups of rats at 0, 1, 5, 125 or 625 ppm for up to 90 days Other groups of rats received either propylthiouracil (PTU; 125 ppm) or amitrole (50 ppm) in their diets as positive controls Only those rats which received ETU at 125 or 625 ppm and those ingesting PTU or amitrole demonstrated a measurable toxic response This toxicity was reflected as an alteration in thyroid function and a significant change in thyroid morphology Ingestion of 625 ppm ETU or 125 ppm PTU resulted in very substantial decrease in serum triiodothyronine (T-3) and thyroxine (T-4) Marked increases in serum thyroid stimulating hormone (TSH) levels were found in the 625 and 125 ppm ETU rats, the 125 PTU rats, and the rats receiving amitrole, each time this hormone was measured Rats which ingested 625 ppm ETU also exhibited a decrease in iodide uptake by the thyroid While a statistically significant increase in serum T-4 and degree of thyroid hyperplasia was observed for rats ingesting 25 ppm ETU for 60 days, normal thyroid hormone levels and thyroid morphology was found in rats on 25 ppm ETU for either 30 or 90 days Based on diochemical and microscopic changes examined, the no-effect level for dietary ETU in this 90-day study is considered to be 25 ppm

Opposite variations in serum t3 and reverse t3 during propylthiouracil treatment of thyrotoxicosis

Abstract: Blood samples for determination of serum total and free reverse triiodothyronine (rT3), triiodothyronine (T3) and thyroxine (T4) were obtained daily in 6 previously untreated thyrotoxic patients during periods of propylthiourazil (PTU) (600 mg per day) or methimazol (MMI) (45 mg per day) administration. PTU induced about 60 per cent increase in both total and free serum rT3. This was accompanied by a rapid decrease in serum T3 and a more gradual decline in serum T4. MMI administration to untreated patients was followed by a gradual parallel decrease in rT3, T3 and T4. Turn from PTU to MMI produced a rapid decrease in serum rT3 and increase in serum T3 in all 6 patients. The relative variations in the free and total concentrations of iodothyronines were practically identical. The increase in serum rT3 after PTU is most likely explained either by enhanced deiodination of T4 to rT3 or by an inhibitory effect of PTU on rT3 degradation.

Influence of hyperthyroidism on the rate of ethanol metabolism in man.

Abstract: The rate of ethanol metabolism was studied in 3 hyperthyroidism patients without therapy and in 2 after 1 week of treatment with propylthiouracil and reserpine. The rate of ethanol metabolism (mg/kg/h

Extrathyroidal effects of propylthiouracil and carbimazole on serum T4, T3, reverse T3 and TRH-induced TSH-release in man.

Abstract: A possible extrathyroidal effect of propylthiouracil (PTU) and carbimazole on serum levels of thyroxine (T4), triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) and on thyrotrophin-releasing hormone (TRH) induced thyrotrophin (TSH) release was estimated in 19 patients with severe hypothyroidism treated with T4. During PTU medication a significant decrease in serum T3 from 90 +/- 16 (SD) to 79 +/- 23 ng/100 ml (P less than 0.01) and a reciprocal increase in serum reverse T3 from 51 +/- 14 (SD) to 58 +/- 20 ng/100 ml (P less than 0.025) were found. No significant changes in serum T4, basal serum TSH or response to TRH could be demonstrated. Carbimazole did not change any of the parameters studied.

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

Abstract: 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 Chronic Treatment of Intact and Hypophysectomized Rats with Thyroid-Stimulating Hormone on the Metabolism of [35S]Methimazole and [36S]Propylthiouracil

Abstract: Chronic treatment of intact rats with various doses of TSH increased the thyroidal 35S accumulation after single doses of [35S jmethimazole (MMI) and [35S]propylthiouracil (PTU). However, no effect on the intrathyroidal breakdown of the drugs was observed. Thus absolute thyroidal levels of unmetabolized MMI and PTU were increased by factors of up to 2 and 3, respectively, compared to the control groups. Simultaneous decreases in the levels of thyroidal total iodine were observed. Hypophysectomized rats showed a marked inhibition of both thyroidal accumulation and oxidation of [35S]- MMI but TSH treatment of hypophysectomized rats restored the accumulation and oxidation to sham-operated and control group levels. The results show that in rats TSH has an important role in the control of thyroidal levels of antithyroid drugs currently used in the treatment of hyperthyroidism

Correlation of reverse-t3 and 3,3′-t2 (t2′) plasma concentrations under physiological and experimental conditions in man

Abstract: T2' plasma levels are measured under different conditions and correlated to the repective rT3 concentrations. Specific RIAs for T2' and rT3 are used. Pharmacological doses of T3 cause an increase of plasma T2'; if T3 or T4 doses are administered to an athyroid patient which cause a similar level of plasma T3 the increase of T2' is much larger during T4 treatment. Cord blood levels of T2' are 2--3-fold higher than in normal adults whereas rT3 concentrations are about 10 times higher than normal. After birth rT3 and T2' levels decrease in about a parallel manner. After a bolus iv injection of 500 microgram rT3, T2' starts to increase as early as 2 min after injection. PTU in therapeutic doses causes a rapid increase of plasma rT3 with a maximum 4 h after ingestion. A dose of 150 mg PTU causes a maximum of about 100% above baseline. T2' also increases but to a lesser degree (about 50% above baseline). We conclude that rT3 is a most important precursor of T2' whereas T3 contributes only to a minor degree to the total T2' production under physiological conditions.

Regulation of thyroidal deiodinase activity.

Abstract: In previous work with human multinodular goiters we had observed widely differing deiodinase activities in different tissue samples of the same thyroid. Since all areas of a single gland must be exposed to an identical plasma TSH level, the findings suggested that TSH is not the only factor regulating deiodinase activity in a goitrous gland. The present investigation was designed to define the relative role of TSH and non-TSH-dependent factors in regulating deiodinase activity of the rat thyroid. After 7 days of goitrogen treatment, the deiodinase activity per g thyroid and per mg DNA was greatly increased with perchlorate (C1O4-) and 6-propyl-2- thiouracil plus C1O4-, and only slightly increased with propylthiouracil alone and with a low iodine diet. Despite the continuous rise of serum TSH with further treatment, deiodinase activity per mg DNA declined to well below peak levels after 1 more week and remained at this only slightly higher than normal value for many weeks irrespective of the goitrogenic re...