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PubMed1980

Audiogenic seizures and cochlear damage in rats after perinatal antithyroid treatment.

The feeding of goitrogens during pregnancy and lactation causes the offspring of rats to be partially deaf and persistently sensitive to audiogenic seizures. The most potent goitrogen, propylthiouracil, caused severe dysfunction and disorganization of the organ of Corti. Adult seizure-susceptible rats showed increased sensitivity to audiogenic seizures when they were fed propylthiouracil.

Acoustic Stimulation↗

PubMed1982

Effects of thyroid status on the structure of the very low density lipoprotein secreted by the perfused liver.

To determine whether hyperthyroidism or hypothyroidism affected the structure of the very low density lipoprotein (VLDL) secreted by the perfused rat liver, rats were pretreated with 0.9% NaCl, T3, or propylthiouracil. The livers were perfused with 0-332 mumol bovine serum albumin-oleate/h for 4 h. The structure of the secreted VLDL was determined by compositional analysis and the use of the fluorescence probe molecules diphenylhexatriene, trans-parinaric acid, and cis-parinaric acid. Compositional analysis indicated that the VLDL secreted by livers from rats pretreated with T3 had lower unsaturated to saturated fatty acid ratios than did controls, regardless of the amount of oleate infused. Fluorescence polarization of diphenylhexatriene indicated that the interior core lipids of VLDL secreted by livers from T3-treated rats were more rigid than those secreted by livers of euthyroid animals. Arrhenius plots of polarization and corrected fluorescence of diphenylhexatriene and trans-parinaric acid, but not cis-parinaric acid, revealed that characteristic temperatures were shifted 8 to 10 C higher in VLDL secreted by livers from rats pretreated with T3. Treatment of rats for 7 days with propylthiouracil under these mild conditions did not alter the structure or composition of the VLDL secreted by the perfused liver. In summary, the lipid changes in the VLDL secreted by perfused rat livers from hyperthyroid animals were consistent with these VLDL being more rigid particles than those secreted by livers from euthyroid rats, independent of the infusion rate of the FFA.

Animals↗

PubMed1983

The effect of thyroid hormones in vitro and in vivo on hypothalamic neurotensin release and content.

Neurotensin (NT) is a hypothalamic peptide which inhibits TSH secretion when administered intraventricularly to the rat. We have studied the effects of TRH, TSH, T3, and rT3 on the release of immunoreactive NT (iNT) from incubations of freshly dissected sections of whole hypothalamic tissue removed from male rats. The effects of T4 or propylthiouracil administration in vivo on hypothalamic iNT content and release was examined as well. T3 (10(-7) M) stimulated iNT release in vitro [45.3 +/- (SE) 1.8 vs. 32.0 +/- 1.9 pg/hypothalamus 30 min-1, P less than 0.005] and a dose-dependent response was observed from 10(-9) M to 10(-7) M; rT3, TRH, and TSH were without effect. T4 administration in vivo caused a reduction in hypothalamic iNT content (5.77 +/- 0.24 vs. 6.57 +/- 0.37 ng/mg protein, P less than 0.05) whereas the induction of hypothyroidism with propylthiouracil and 131I resulted in an increase in iNT content (8.25 +/- 0.27 ng/mg protein, P less than 0.001). Basal release of hypothalamic iNT was similar in all three groups but 58 mM KCl-induced release from hypothyroid hypothalami was impaired. These results indicate a positive influence of T3 on hypothalamic iNT release and have led us to the hypothesis that T3 exerts a negative feedback effect on its own secretion via inhibition of TSH release by NT.

Animals↗

PubMed1984

Metabolism of 3,3'-diiodothyronine in rat hepatocytes: interaction of sulfation with deiodination.

Production of 3,3'-diiodothyronine (3,3'-T2) is an important step in the peripheral metabolism of thyroid hormone in man. The rapid clearance of 3,3'-T2 is accomplished to a large extent in the liver. We have studied in detail the mechanisms of this process using monolayers of freshly isolated rat hepatocytes. After incubation with 3,[3'-125I]T2, chromatographic analysis of the medium revealed two major metabolic routes: outer ring deiodination and sulfation. We recently demonstrated that sulfate conjugation precedes and in effect accelerates deiodination of 3,3'-T2. In media containing different serum concentrations the cellular clearance rate was determined by the nonprotein-bound fraction of 3,3'-T2. At substrate concentrations below 10(-8) M 125I- was the main product observed. At higher concentrations deiodination became saturated, and 3,3'-T2 sulfate (T2S) accumulated in the medium. Saturation of 3,3'-T2 clearance was found to occur only at very high (greater than 10(-6)M) substrate concentrations. The sulfating capacity of the cells exceeded that of deiodination by at least 20-fold. Deiodination was completely inhibited by 10(-4) M propylthiouracil or thiouracil, resulting in the accumulation of T2S while clearance of 3,3'-T2 was little affected. No effect was seen with methimazole. Hepatocytes from 72-h fasted rats showed a significant reduction of deiodination but unimpaired sulfation. Other iodothyronines interfered with 3,3'-T2 metabolism. Deiodination was strongly inhibited by 2 microM T4 and rT3 (80%) but little by T3 (15%), whereas the clearance of 3,3'-T2 was reduced by 27% (T4 and rT3) and 12% (T3). It is concluded that the rapid hepatic clearance of 3,3'-T2 is determined by the sulfate-transferring capacity of the liver cells. Subsequent outer ring deiodination of the intermediate T2S is inhibited by propylthiouracil and by fasting, essentially without an effect on overall 3,3'-T2 clearance.

Animals↗

PubMed1986

Increased follicular heterogeneity in experimental colloid goiter produced by refeeding iodine excess after thyroid hyperplasia.

Delayed morphological changes induced in mouse hyperplastic thyroid by refeeding iodine were analyzed by light and electron microscopy, stereology, and autoradiography. Thyroid hyperplasia was induced by a low iodine diet supplemented with 0.25% propylthiouracil for 10 days. Involution was obtained by discontinuing the propylthiouracil and returning either to a moderate iodine diet [(MID) 1 microgram I/day] or to an iodine-rich diet [(HID) 10 micrograms I/day] for 40 days. In other experiments, three cycles of hyperplasia (8 days) and subsequent involution (8 days) with MID or HID were brought about. Control animals were fed MID or HID. All animals were killed when 12-14 weeks old after injection of 10-50 microCi 125I. Double labeling, with repeated injections of [3H]thymidine from day 0 to day 7 of involution followed by 125I injection 4 h before killing, was also performed. When involutions were performed with MID, most morphological variables returned to control values. However, when involution was brought about with HID, the glandular weight, the number of follicles, and the relative volume of follicular lumina remained larger than in controls. Moreover, the 125I-labeling pattern of the follicles was altered. The proportions of unlabeled, and unevenly or partly labeled, follicles, which were fewer than 5% in control groups, represented 25-35% of all follicles after involution with HID, whereas they were unchanged with MID. In unlabeled follicles the epithelium was flattened, with a reduced number of microvilli. Partly labeled follicles were of two types. In some follicles a persistent ring reaction was observed, suggesting an abnormally slow mixing of thyroglobulin. In others, the 125I labeling was restricted to areas adjacent to the apex of a reduced number of cells, suggesting that some cells were iodinating thyroglobulin, whereas others were not. There was no relationship between the follicular 125I labeling and the frequency of [3H]thymidine-labeled cells. These results indicate that refeeding iodine excess after hyperplasia leads to the formation of a colloid goiter with new follicles, and to an increased heterogeneity of iodine metabolism among follicles and among cells.

Animals↗

PubMed1988

Inhibition of uptake of thyroid hormone into rat hepatocytes by preincubation with N-bromoacetyl-3,3',5-triiodothyronine.

To investigate whether affinity coupling of N-bromoacetyl-T3 (BrAcT3) to the T3 membrane carrier results in an inhibition of transport of T3 into the cell, rat hepatocytes in monolayer were incubated for 2 h at 21 C with 1.3 mumol/liter BrAcT3 in medium without protein. After extensive washing, cells were incubated during 20 h at 37 C with [125I]T3 in medium with 0.5% BSA, and products in supernatants were analyzed by LH-20 column chromatography. In addition the apparent affinity constant (Km) and maximal uptake velocity (Vmax) of the high affinity uptake process were estimated using 1 min incubations of hepatocytes with various concentrations of T3. In control experiments (i.e. without BrAcT3 affinity coupling) about 57% of the added T3 was cleared from the medium and further metabolized, 85% of the cleared T3 reappeared in the medium as I-, 15% as conjugates. Addition of propylthiouracil during the 20 h incubation with T3 strongly inhibited deiodination, without a change in T3 clearance. Because T3 is sulfated before deiodination, a concomitant rise in conjugates was observed. Addition of ouabain to control cells during the 20 h incubation with T3 strongly inhibited uptake, with a parallel decrease in I- and conjugate formation. After affinity coupling of BrAcT3, T3 clearance was inhibited (by 30% P less than 0.001). Since I- production was more depressed (by 73%) than T3 clearance, with some rise in conjugate formation (P less than 0.001), inhibition of deiodinase by BrAcT3 also took place. The effects of BrAcT3 and ouabain on uptake of T3 appeared to be additive as were the effects of propylthiouracil and BrAcT3 on deiodination. After affinity coupling of BrAcT3, the Km of T3 uptake did not change significantly; however Vmax was 54% lower (P less than 0.025) indicating a noncompetitive inhibition of the transport system. Preincubation of the cells with N-acetyl-T3 does not alter the characteristics of uptake of T3 by rat hepatocytes as compared to controls, indicating that no binding of this compound occurs. It is concluded that preincubation of hepatocytes with BrAcT3 diminished I- formation from T3; 50% of this inhibition is due to decreased membrane transport and 50% by reduction of deiodination. Inhibition of membrane transport by BrAcT3 is substantiated by a 54% lower Vmax without a significant change in Km as compared to control. The effect of transport of thyroid hormone on metabolism stresses the importance of the membrane carrier in the translocation process.

Affinity Labels↗

PubMed1989

The postnatal development of sarcoplasmic reticulum Ca2+ transport activity in skeletal muscle of the rat is critically dependent on thyroid hormone.

We investigated the role of thyroid hormone in the postnatal development of Ca2+ transport activity of sarcoplasmic reticulum in skeletal muscle (m. gastrocnemius-plantaris). With a Ca2+-stat method using the fluorescent dye fura 2 as Ca2+ indicator, we determined the oxalate-supported maximal Ca2+ uptake activity of sarcoplasmic reticulum in whole muscle homogenates from neonatal rats. Expressed per g tissue wet wt, the activity increased nearly 10-fold during the first 8 weeks after birth, following which time a plateau was reached. This development was absent in hypothyroid pups, in which the level of Ca2+ uptake activity remained constant at 10% of the normal adult value for at least 8 weeks. When the mothers were given 0.05% propylthiouracil in the drinking water 1 week before parturition, these pups ceased to grow after 4 weeks, had a reduced muscle protein content and a characteristic cretinous appearance. The effects of hypothyroidism could be reversed by T3 treatment (0.5 micrograms/100 g BW, daily) starting 1 or 6 weeks after birth. Treatment with bovine GH (0.1 or 0.5 IU/100 g BW; daily) starting on day 5 stimulated body growth, particularly of muscle, but was without effect on the failing development of Ca2+ uptake activity. The postnatal rise in citrate synthase and succinate dehydrogenase activities was impaired in the hypothyroid group, but lactate dehydrogenase and creatine kinase activities rose continuously, although at a reduced rate. T3 treatment also reversed these effects of propylthiouracil. At the higher dosage used bovine GH appeared to stimulate the accumulation of creatine kinase. We conclude that the failing postnatal development of sarcoplasmic reticulum Ca2+ transport activity in hypothyroidism is not secondary to the absence of GH, nor is it part of a general, indiscriminate effect, but, rather, that it indicates an absolute requirement of thyroid hormone for this particular aspect of muscle differentiation.

Animals↗

PubMed1989

Thyroxine, triiodothyronine, and reverse triiodothyronine processing in the cerebellum: autoradiographic studies in adult rats.

Well confirmed evidence has demonstrated that the cerebellum is an important target of thyroid hormone action during development. Moreover, the presence of nuclear receptors and strong 5'-deiodinase activity in cerebella of adult rats have suggested that this region may continue to respond to thyroid hormones during maturity. Recent autoradiographic observations have focused attention on the cerebellar granular layer, in that [125I]T3 administered iv to adult rats was found to be selectively and saturably concentrated there. To determine the specificity of iodothyronine localization in the granular layer, we have now compared film autoradiographic observations made after iv [125I]T4 and iv [125I]rT3 with those found after iv [125I]T3. The results demonstrated that, as in the case of the latter hormone, labeling within the cerebellar cortex after iv [125I]T4 was both selective and saturable. Moreover, except for a lag in time to resolution and a longer retention time, the distribution of cerebellar radioactivity after iv labeled T4 was qualitatively similar to that seen after iv [125I]T3. However, the ability of T4 to become differentially concentrated in the granular layer of cerebellum was absolutely dependent on its ability to be converted intracerebrally to T3. Thus, pretreatment with ipodate, which blocks brain 5'-deiodinase activity and, therefore, the intracerebral formation of T3 from T4, completely prevented cerebellar granular layer labeling after iv [125I]T4 even though it did not interfere with differential labeling of this region by iv delivered [125I]T3. In the same experiments, propylthiouracil, a potent peripheral, but not central, 5'-deiodinase inhibitor, had no qualitative effect on the distribution of either T4 or T3 in cerebellum. By contrast with the results obtained after administering labeled T3 or T4, brain labeling after iv delivered [125I]rT3 was found to be no different from that produced by markers of cerebral blood flow, which rapidly enter and leave the brain without becoming incorporated into brain cells. This was so even during treatment with propylthiouracil and ipodate, both of which markedly prolonged the normally brief residence time of this iodothyronine in serum and brain. Overall, the autoradiographic results served to highlight the importance of the morphological approach for investigating thyroid hormone action and metabolism in brain. They demonstrated that only T3, whether entering as such from the circulation or formed in situ from T4 (but neither T4 itself nor iv administered rT3) was strongly, selectively, and saturably concentrated in the cerebellar granular layer of adult rats.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Severe but not mild alterations of thyroid function modulate the density of thyroid-stimulating hormone receptors in the rat thyroid gland.

TSH initiates its action by binding to specific membrane receptors' thyroid cells and induces activation of the adenylate cyclase-cAMP cascade. The factors involved in the regulation of TSH receptors are poorly known, except for the TSH dose-dependent regulatory effect. The fact that the thyroid gland of Graves' patients has a normal density of TSH receptors with suppressed TSH and high T4 and T3 levels suggests a modulatory role of thyroid hormones on TSH receptors. To evaluate this hypothesis, the density of TSH receptors and the activity of adenylate cyclase were determined in the thyroid membranes from hyperthyroid and hypothyroid adult male rats; they were rendered hyperthyroid either with bovine TSH, TRH, or T3 for 7 days and hypothyroid by propylthiouracil treatment or by hypophysectomy. NaCl was given to the control group. Plasma T4, T3, and TSH were also quantified. Bovine TSH and TRH treatments induced mild hyperthyroidism with a small goiter and a 50% reduction in the density of TSH receptors due to hyperstimulation of the gland by either exogenous or endogenous high TSH levels. Severe hyperthyroidism caused by T3 treatment resulted in low T4, high T3, and suppressed TSH thyrocyte stimulation; it was associated with a significant increase in the number of TSH receptors (29.6 +/- 2.3 vs. control 17.9 +/- 1.7 mU TSH/mg protein). These last results suggest a putative positive effect of T3 on TSH receptors. To confirm this effect, hypothyroid rats were investigated. Severe primary hypothyroidism due to propylthiouracil treatment was associated with a large goiter, high plasma TSH levels (11.8 +/- 1.2 vs. control 1.5 +/- 0.1 mU TSH/ml), low plasma T4 and T3, and a 70% reduction in TSH receptors, confirming the down-regulatory effect of high TSH on the thyroid cell. However, in hypophysectomized rats, a 45% reduction in the density of TSH receptors was also observed in the absence of TSH. Injections of either TSH or T3 to these hypophysectomized rats restored a normal number of TSH-binding sites, and simultaneous TSH and T3 treatments resulted in a mildly additive effect in the number of TSH receptors, which was slightly greater than that of the controls. No important changes were found in the adenylate cyclase activity in the thyroid membrane preparations from hyperthyroid and hypothyroid rats despite variations in the density of TSH receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenylyl Cyclases↗

PubMed1995

Thyroid hormones rapidly and stringently regulate the messenger RNA levels of the thyrotropin-releasing hormone (TRH) receptor and the TRH-degrading ectoenzyme.

The responsiveness of adenohypophyseal target cells for the hypothalamic neuropeptide TRH is known to change depending on the hormonal and physiological conditions of the organism. We describe here the effects of thyroid hormones on the transcript levels of the TRH receptor, the TRH-degrading ectoenzyme, and TSH in rat pituitary, as revealed by Northern blot analysis. After a single injection of T3 (30 micrograms/100 g BW), the transcript levels of the TRH receptor decreased transiently, reaching 35% of control values 4 h after injection, and returned to basal levels within 24 h. In contrast, the messenger RNA (mRNA) levels of the TRH-degrading ectoenzyme increased more dramatically in response to the same hormonal stimulus. Maximal levels (> 10 times above the control value) were present from 6-24 h after the injection, returning to basal values within 96 h. For both transcripts, the observed effects changed in a dose-dependent manner, but the mRNA levels of the TRH-degrading ectoenzyme were more tightly regulated. Under the experimental conditions used, the mRNA levels of PRL and GH were not affected by the application of T3, and those of alpha-subunit exhibited only minor reductions. The TSH beta transcripts however, decreased rapidly in length and slowly in concentration, finally reaching almost undetectable levels 48 h after the injection. Subsequently, newly synthesized TSH beta mRNA, the same size as the transcripts from euthyroid rats, could be detected 96 h after treatment with T3. Upon treatment of the animals with the mild goitrogenic agent n-propylthiouracil (200 mg/liter drinking water), a fast reduction in the transcript levels of the TRH-degrading ectoenzyme became evident. Within 1 day, mRNA levels decreased to less than 50% of control values. At this stage, no effects were observed on the transcript levels of either the TRH receptor or TSH beta. After 4 days of n-propylthiouracil treatment, the mRNA levels of the enzyme decreased further to 15% of control values, whereas the transcript concentrations of the TRH receptor and TSH beta rose by factors of 2 and 3.3, respectively. The extremely stringent regulation of the TRH-degrading ectoenzyme, a mirror image of that of the TRH receptor, strongly suggests that this enzyme represents an important regulatory element, controlling the stimulation of TRH target cells and, thus, adenohypophyseal hormone secretion.

Aminopeptidases↗

PubMed1997

Rainbow trout liver expresses two iodothyronine phenolic ring deiodinase pathways with the characteristics of mammalian types I and II 5'-deiodinases.

Deiodinases are major determinants of thyroid hormone tissue availability and disposal. The knowledge of the expression of these enzymes in lower species is important to understand evolutionary and ontogenetic aspects of thyroid hormone action and metabolism. Here we have studied outer ring deiodination in the trout liver using both reverse T3 (rT3) and T4 as substrates. The use of rT3 disclosed two enzymatic components with the characteristics of mammalian types I and II 5'-deiodinases. The high rT3-K(m) type I 5'-deiodinase activity (180 nM) has a low cofactor requirement (5 mM dithiothreitol) and is relatively sensitive to propylthiouracil inhibition, whereas the low rT3-K(m) activity was akin to the outer ring deiodination of T4 in these regards. The use of T4 exhibited only a single type of activity with a low K(m) (0.63 nM), a relatively high cofactor requirement (25 mM dithiothreitol), and propylthiouracil-resistance. Teleosts constitute a unique example of type II activity expression in the liver of an adult vertebrate. Furthermore, the Vmax of this enzyme is as high as that found in comparable homogenates from hypothyroid mammalian tissues, whereas the Vmax of the type I activity is lower than that of mammalian liver. These findings are in consonance with the peculiar kinetics of T3 in trout liver, kinetics remarkably similar to those of the mammalian pituitary, cerebral cortex, and brown adipose tissue, which also preferentially express type II deiodinase.

Animals↗

PubMed1997

The role of the active site cysteine in catalysis by type 1 iodothyronine deiodinase.

Type 1 iodothyronine deiodinase (deiodinase 1) is a selenoenzyme that converts the prohormone T4 to the active thyroid hormone T3 by outer ring deiodination or to the inactive metabolite rT3 by inner ring deiodination. Although selenocysteine has been demonstrated to be essential for the biochemical profile of deiodinase 1, the role of a highly conserved, active site cysteine (C124 in rat deiodinase 1) has not been defined. The present studies examined the effects of a Cys124Ala mutation on rat deiodinase 1 enzymatic function and substrate affinity. At a constant 10-mM concentration of dithiothreitol (DTT), the C124A mutant demonstrated a 2-fold lower apparent maximal velocity (Vmax) and Km for rT3 (KmrT3) than the wild type for outer ring deiodination, whereas the Vmax/Km ratio was unchanged. Similarly, the apparent Vmax and KmT3 sulfate for inner ring deiodination were 2-fold lower in the C124A mutant relative to those in the wild type, with no change in the Vmax/Km ratio. The C124A mutant exhibited ping-pong kinetics in the presence of DTT, and substitution of the active site cysteine increased the KmDTT by 14-fold relative to that of the wild-type enzyme, with no significant effects on KmrT3 or Vmax. The C124A mutant was inhibited by propylthiouracil in an uncompetitive fashion and exhibited a 2-fold increase in K(i)propylthiouracil compared with that of the wild type. KmrT3 was also reduced for the C124A mutant when 5 mM reduced glutathione, a potential physiological monothiol cosubstrate, was used in outer ring deiodination assays. These results demonstrate that thiol cosubstrate interactions with C124 in type 1 deiodinase play an important role in enhancing catalytic efficiency for both outer and inner ring deiodination.

Amino Acid Sequence↗

PubMed1998

ROR alpha gene expression in the perinatal rat cerebellum: ontogeny and thyroid hormone regulation.

Deficiency of thyroid hormone (TH) during the perinatal period results in severe neurological abnormalities in rodent cerebellar development. However, the molecular mechanisms of TH action in the developing cerebellum are not fully understood. Of note, a mutant mouse, staggerer, in which the orphan nuclear hormone receptor ROR alpha gene is disrupted, exhibits cerebellar abnormalities similar to those seen in the hypothyroid animals, despite normal thyroid function. We, therefore, speculated that TH (tetraiodo-L-thyronine; T4) may regulate ROR alpha gene expression, which then may regulate genes essential for normal brain development. To test this hypothesis, we studied the changes in ROR alpha gene expression in perinatal hypothyroid rat cerebellum and the effect of TH replacement using Northern blot analysis, ribonuclease protection assay and in situ hybridization histochemistry. During cerebellar development, an approximately 3-fold increase in the cerebellar content of ROR alpha messenger RNA (mRNA) was seen in both propylthiouracil-treated, and propylthiouracil-treated and T4-replaced animals. However, the increase was accelerated when T4 was injected, although the ROR alpha mRNA content was identical, with or without T4, by 30 days after birth (P30). In contrast, T4 treatment suppressed the TH receptor alpha1 and c-erbA alpha2 mRNA content by P30; retinoic acid X receptor-beta mRNA content was not influenced by thyroid status. A significant hybridization signal for ROR alpha mRNA was seen only over Purkinje cells in the cerebellar cortex by in situ hybridization histochemistry. These results indicate that TH alters the timing of expression of the ROR alpha gene in the Purkinje cells of the cerebellar cortex, which may, in turn, influence Purkinje cell differentiation.

Amino Acid Sequence↗

PubMed2002

Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself?

Because we previously reported that T3 and 3,5-diiodo-L-thyronine (3,5-T2) both increase resting metabolic rate (RMR), 3,5-T2 could be another thyroidal regulator of energy metabolism. This effect of 3,5-T2 is evident in rats made hypothyroid by propylthiouracil and iopanoic acid, not in normal euthyroid (N) rats. Possibly, under euthyroid conditions, active 3,5-T2 may need to be formed intracellularly from a precursor such as T3. We tested this hypothesis by giving a single injection of T3 to N rats and comparing the time course of the variations in RMR with those of the changes in the serum and hepatic levels of 3,5-T2. Acute injection had an evident effect on RMR, 25 h earlier, in N rats than in rats made hypothyroid by propylthiouracil and iopanoic acid, maximal values (+40%) being reached in the former at 24-26 h. In N rats, the simultaneous injection of actinomycin D with the T3 inhibited the late part of the effect (after 24 h) more strongly than the early part (14-24 h). In serum and liver, 3,5-T2 levels were increased significantly at 12-24 h after T3 injection into N rats, a time at which RMR was rising rapidly to peak. These results seem to indicate that when T3 is injected into N animals, not all the effects on RMR are attributable to T3 itself, the early effect presumably being largely because of its in vivo deiodination to 3,5-T2. Because the effects of T3 and 3,5-T2 are additive, in N rats, the two iodothyronines probably cooperate in vivo to determine the total metabolic rate.

Animals↗

PubMed1998

Effects of octreotide on propylotiouracil-induced goiter in rats: a quantitative evaluation.

To evaluate the possible antigoitrogenic effect of somatostatin, the influence of long-acting somatostatin analog--octreotide--on experimental goiter developed in rats treated with propylthiouracil was examined. Goiter formation was assessed by measurement of the main histological compartments of the thyroid as well as by morphometric analysis of the vascularization and blood supply of the gland. Although treatment with octreotide did not prevent the goiter formation, it clearly reduced blood supply and vascularization of the thyroid and counteracted propylthiouracil-induced increase in the relative volume of follicular epithelium. To conclude, the somatostatin analog--octreotide--is effective in reduction of goiter vascularisation. This finding provides a rationale for the clinical trials of the treatment of hypervascular goiter by somatostatin analogs.

Animals↗

PubMed1986

Thyroid hormone autoantibodies (THAA) in two cases of Graves' disease: effects of antithyroid drugs, prednisolone, and subtotal thyroidectomy.

Changes in titers of serum thyroid hormone autoantibodies (THAA) and anti-thyroglobulin (Tg) antibodies during treatment with antithyroid drugs (methimazole and propylthiouracil) were examined in two cases of Graves' disease. Effects of prednisolone and subtotal thyroidectomy were also investigated in one case (case 1). Initially both cases had only anti-T4 autoantibodies in their serum. During methimazole therapy, the titer of anti-T4 autoantibodies increased in both cases, and anti-T3 autoantibodies became detectable and their titer increased in case 2. The influence of propylthiouracil on the titer of THAA was not clear. Both prednisolone plus methimazole therapy and subtotal thyroidectomy decreased the level of anti-T4 autoantibodies in case 1. There was a significant correlation between titers of THAA and anti-Tg antibodies in both cases, although titers of anti-Tg antibodies in case 1 stayed within the normal range throughout the investigation period. These results indicate that methimazole treatment could induce and/or enhance the production of THAA and THAA are antibodies against thyroid hormone-containing Tg molecule.

Autoantibodies↗

PubMed1988

Mechanism of thioamide antithyroid drug associated hypoprothrombinemia.

The thioamide class of antithyroid drugs has been associated with the development of hypoprothrombinemia. Two drugs in this class, propylthiouracil and methimazole, resemble the methyltetrazole-thiol leaving group of certain cephalosporin antibiotics. Both were found in vitro to inhibit the vitamin K dependent step in clotting factor synthesis, the gamma-carboxylation of glutamic acid with 50 per cent inhibitory concentrations of 2 mM for propylthiouracil and 0.1 mM for methimazole. Methimazole was also found to inhibit vitamin K epoxide reductase, an enzyme related to the carboxylation reaction, with a 50 per cent inhibitory concentration of 25 uM. In vivo methimazole, administered twice at a dose of 500 mg/kg to rats on a vitamin K deficient diet produced hypoprothrombinemia. These results suggest that the mechanism of hypoprothrombinemia associated with thioamide antithyroid drugs may be similar to the mechanism of hypoprothrombinemia associated with cephalosporins which contain the methyltetrazole-thiol leaving group.

Amides↗

PubMed1986

Thyroxine monodeiodination in normal human kidney tissue in vitro.

The present study deals with thyroxine monodeiodination in normal human kidney. To allow for comparison with previous reports, the present methods are similar to those used by others in rat tissue studies. The microsomal cell fraction of normal human kidney tissue was obtained by differential ultracentrifugation. The microsomes were incubated under various conditions and the deiodination products assayed with radioimmunoassay. A type I 5'-monodeiodinase was demonstrated, pH optimum around 6.5. Competitive inhibition was observed of T3 generation from T4 by rT3 with a Km of 3.0 microM and a Ki of 4 microM. Vmax was 26.1 pmol/min/mg protein. Likewise rT3 was generated from added T4, but it was rapidly degraded, while T3 was relatively stable as is the case in rat tissue preparations. Propylthiouracil inhibited 5'-deiodination in a dose dependent fashion with complete abolishment of deiodination at propylthiouracil concentration of 10(-4) M. Ipodate inhibited the reaction with complete inhibition at 10(-2) M. The data demonstrate that a human kidney particulate cell-fraction contained considerable amounts of T4 deiodinases, very similar to the type I deiodinase of various rat tissue, although the handling of rT3 and the inhibitory action of this iodothyronine on T4 to T3 conversion seem to be slightly different in the two species.

Humans↗