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PubMed1993

Effects of thyroxine on avian moulting may not involve prior conversion to tri-iodothyronine.

The comparative effects of equimolar doses of thyroxine (T4) and tri-iodothyronine (T3) and of the inhibition of peripheral monodeiodination were studied on feather regeneration and moult in thyroidectomized and intact adult male spotted munia (Lonchura punctulata). T4 was significantly more effective than T3 at all dose levels in inducing feather regeneration in thyroidectomized birds. Suppression of monodeiodination by iopanoic acid (IOP) was not accompanied by a suppression of T4-induced feather regeneration in thyroidectomized birds and IOP alone was without effect in thyroidectomized birds. Long-term treatment of intact birds with IOP accelerated the process of moulting by about 3 months. These findings question the prevailing concept that T3 is the finally active biological compound and T4 a mere precursor.

Animals↗

PubMed1990

Ontogeny and perinatal modulation of gene expression in rat brown adipose tissue. Unaltered iodothyronine 5'-deiodinase activity is necessary for the response to environmental temperature at birth.

We have performed a sequential study on the abundance of the mRNA for uncoupling protein (UCP), subunit II of cytochrome-c oxidase (COII) and lipoprotein lipase in brown adipose tissue during the fetal and postnatal periods. Moreover, we have determined whether these parameters can be modulated by ambient temperature in the early hours after birth, and at which point in development this sensitivity first appears. UCP gene expression in the fetal and neonatal period has particular features when compared with overall mitochondriogenesis (COII mRNA expression) or with the expression of lipoprotein lipase mRNA. There is a specific induction of UCP gene expression between days 18 and 19 of pregnancy followed by a specific increase of UCP gene expression in utero and a further increase after birth. The acquisition of the physiological apparatus capable of the response to UCP and lipoprotein lipase gene expression to the environmental temperature is not achieved until the last day of fetal development. This result suggests that mechanisms of beta-adrenergic modulation of gene expression in brown fat are already established at birth. From an experiment on iopanoic acid treatment of pregnant mothers, it was concluded that iodothyronine 5'-deiodinase activity is not necessary for the expression of the mRNAs for UCP, COII and lipoprotein lipase in the fetus whereas it is necessary for the acquisition of temperature sensitivity to these parameters at birth.

Adipose Tissue, Brown↗

PubMed1998

Comparison of the effects of thyroxine and triiodothyronine on protein turnover and apoptosis in primary chick muscle cell cultures.

Primary chick muscle cells were treated with physiological level of thyroxine (T4) or triiodothyronine (T3) to examine the effects of the hormones on growth, protein turnover, and apoptosis of the cells. Creatine kinase activity, as an index of differentiation, was increased by both T4 and T3. Even when the conversion from T4 to T3 was blocked by iopanoic acid, T4 increased creatine kinase activity. The rate of protein degradation estimated from [3H] tyrosine release was increased by T3 but not by T4. DNA cleavage and fragmentation, as indices of apoptosis, were induced by T3 but not by T4. These results show that T4 stimulates cell differentiation but not protein degradation and apoptosis in primary chick muscle cells, while all events are stimulated by T3.

Animals↗

PubMed2000

Helical CT cholangiography with oral cholecystographic contrast material.

Twenty asymptomatic volunteers underwent helical computed tomographic (CT) cholangiography 10-12 hours after ingesting iopanoic acid. Three observers assessed the images for the extent of bile duct visualization and image quality. The common bile duct and common hepatic duct were adequately visualized in 19 (95%) subjects. Helical CT cholangiography with oral cholecystographic contrast material is feasible and deserves further clinical studies.

Administration, Oral↗

PubMed1993

Thyroxine 5-deiodinase in human brain tumors.

To determine whether human brains contain deiodinating pathways, we studied the activity of T4 5-monodeiodinase (5-D) in 20 human brain tumors obtained intraoperatively, including astrocytoma (10), meningioma (4), oligodendroglioma (2), glioblastoma (2), medulloblastoma (1), and malignant lymphoma (1). Mitochondrial-microsomal fractions prepared from these tumor tissues were used as the source of T4 5-D. Each sample was incubated with 32.2 nmol/L T4 and 30 mmol/L dithiothreitol at 37 C for 90 min. T4 5-D activity was measured by the production of rT3 from T4 with a RIA. T4 5-D activity was found in 6 of 10 astrocytomas, 2 oligodendrogliomas, 1 of 2 glioblastomas, and 1 malignant lymphoma. This activity depended on protein concentration, incubation time, incubation temperature, and pH of the incubation mixture. It was also heat labile. T4 5-D was not inhibited by 1 mmol/L propylthiouracil, but was inhibited by iopanoic acid and aurothioglucose in a dose-dependent manner. The apparent Km and maximum velocity for T4 5-D at 30 mmol/L dithiothreitol were 106.6 nmol/L and 22.7 pmol/mg protein.h, respectively. These data suggest that human gliomas (and probably malignant lymphomas) contain T4 5-D activity, which is similar to type III enzyme activity in the rat. T4 5-D may regulate the intracellular concentration of thyroid hormone in gliomas.

Adult↗

PubMed1988

The effect of acute treatment with two goitrogens on plasma thyroid hormones, testosterone and testicular morphology in adult male rats.

1. Hypothyroidism was induced in adult male rats by treatment with either iopanoic acid (IOP) or propylthiouracil (PTU). The hypothyroid animals were maintained for a period of 4 weeks. 2. The IOP and PTU treatments produced drastically different thyroid hormone profiles during the treatment period. 3. Serum testosterone levels were not significantly different from controls in either of the goitrogen-treated groups. 4. Testes weights and germ cell populations were not significantly different from controls in either of goitrogen treated groups. 5. Seminiferous tubule morphology showed no significant variation in lumen size or basal lamina structure in either of the treatment groups when compared to the controls.

Animals↗

PubMed1997

Different experimental conditions which regulate type II 5'-deiodinase mRNA in rat Harderian gland.

In the present study, we describe the modifications in the expression of type II 5'deiodinase activity (5'D) in Xenopus laevis oocytes by injection of polyadenylated (poly A) mRNA from hypothyroid rat Harderian gland. The time-course study showed that the expression of the enzyme was dependent on time. Thus, enzyme activity was observed in oocytes 6 and 12 hours after the injection with poly A mRNA, reaching a maximal value at 24 hours. The activity was partially inhibited by 6-n-propyl-thiouracil, completely inhibited by iopanoic acid and exhibited a higher affinity for the T4 (Km=1.5 nM) than rT3 (Km=20 nM). The expression of the enzyme was modified in different experimental conditions: (a) exhibited diurnal variations with maximal peak values at night, (b) was inhibited by light at night and, (c) was activated by isoproterenol. On the other hand, we have also identified, for the first time, the size of mRNA capable of inducing 5'D in rats.

Adrenergic beta-Agonists↗

PubMed1991

The ontogeny of iodothyronine deiodinase systems in liver and intestine of the rat.

The ontogeny of the iodothyronine deiodinase systems has been studied by several investigators in recent years, but our understanding of the subject is far from complete. The present study was conducted to obtain kinetic information concerning 5' deiodinase (5'D) and 5 deiodinase (5D) activities in fetal rat liver and intestine, and to examine reduced glutathione (GSH)-activated 5'D activity in the two tissues. When dithiothreitol (DTT) was used as cofactor in concentrations up to 100 mM, 5'D activity was not clearly detected in liver or intestine until day 16 of gestation. Activity increased markedly in both tissues between fetal day 18-21, due primarily to an increase in maximum velocity (Vmax) of the enzyme. However, whereas 5'D activity was much higher in adult liver than in fetal liver [due to both an increase in Vmax and a decrease in the Michaelis-Menten constant (Km)], activity was barely detectable in adult intestine. When GSH was used as cofactor, the temporal development of activity in both tissues was comparable to that observed with DTT, but kinetic values were very different; with DTT mean values for Vmax in liver ranged from 3.7-1264 pmol I-/h.mg protein, and values for Km ranged from 0.1-0.5 microM; with GSH, values for Vmax ranged from 0.4-16.7 pmol I-/h.mg protein, and values for Km were less than 1 nM. A comparable difference was observed also in intestine. When either DTT or GSH was used as cofactor, 5'D activity was inhibited in the presence of 6n-propyl-2-thiouracil or iopanoic acid. Using T3 as substrate it was found that 5D activity was much higher in intestine than in liver, and the amount of 5D activity in intestine paralleled that in brain in that it was much higher in fetal than in adult tissue. Moreover, values for Vmax and Km in fetal intestine were comparable to those in fetal brain. These findings suggest that thyroid hormone is important in the developing rat intestine and raise the possibility that GSH could be the activator of 5'D systems in vivo.

Aging↗

PubMed2005

Electrospray ionization mass spectrometry as a tool for determination of drug binding sites to human serum albumin by noncovalent interaction.

Most proteins in blood plasma bind ligands. Human serum albumin (HSA) is the main transport protein with a very high capacity for binding of endogenous and exogenous compounds in plasma. Many pharmacokinetic properties of a drug depend on the level of binding to plasma proteins. This work reports studies of noncovalent interactions by means of nanoelectrospray ionization mass spectrometry (nanoESI-MS) for determination of the specific binding of selected drug candidates to HSA. Warfarin, iopanoic acid and digitoxin were chosen as site-specific probes that bind to the main sites of HSA. Two drug candidates and two known binders to HSA were analyzed using a competitive approach. The drugs were incubated with the target protein followed by addition of site-specific probes, one at a time. The drug candidates showed predominant affinity to site I (warfarin site). Naproxen and glyburide showed affinity to both sites I and II. The advantages of nanoESI-MS for these studies are the sensitivity, the absence of labeled molecules and the short method development time.

Binding Sites↗

PubMed2004

Effects of tetraiodothyronine and triiodothyronine on hamster cheek pouch microcirculation.

The aim of the present study was to assess the effects of topically applied triiodothyronine (T(3)) and thyroxine (T(4)) on the arterioles of hamster cheek pouch microcirculation in vivo. Microvessels were visualized using a fluorescent microscopy technique. Topical application of T(3) (3.08, 30.8, 61.5, 307, 615, and 6,150 nM/l) consistently induced dose-dependent dilation of arterioles within 2.0 +/- 0.5 min of administration. The application of T(4) (150, 257, 514, and 5,140 nM/l) caused different dose-dependent effects: dilation at the three lower doses within 16 +/- 2 min and rhythmic diameter changes at the highest dose. Aging of hamsters did not alter the arteriolar responses to T(3) and T(4). T(3)-induced dilation was countered by the inhibition of nitric oxide synthase with N(G)-nitro-L-arginine-methyl ester or N(G)-nitro-L-arginine. Iopanoic acid (IPA), which inhibits types I and II 5'-deiodinase, abolished the dilation elicited by 514 nM T(4) but did not affect T(3)-dependent dilation. 6-Propyl-2-thiouracil (PTU), which inhibits type I 5'-deiodinase only, did not affect the dilation induced by T(4). IPA and PTU did not impair arteriolar dilation induced by acetylcholine or sodium nitroprusside. These results indicate that T(3) induces arteriolar dilation, likely through nitric oxide release. The local conversion of T(4) to T(3) appears to be crucial for the dilation induced by T(4).

Animals↗

PubMed1990

Inhibition of intermediary metabolism by amiodarone in dog thyroid slices.

Amiodarone, an iodine-containing antiarrhythmic drug, has been reported to interfere with thyroid function and thyroid hormone metabolism. We studied the effects of amiodarone on basal and agonist [thyroid-stimulating hormone (TSH), phorbol ester, or carbachol]-stimulated glucose oxidation, 32PO4 incorporation into phospholipids, and adenosine 3',5'-cyclic monophosphate (cAMP) concentration in dog thyroid slices. Slices were preincubated with amiodarone at 37 degrees C for 1 h before the addition of agonist and the appropriate radioisotope. cAMP stimulation was measured after 20 min, glucose oxidation for 45 min, and 32PO4 incorporation into phospholipids for 2 h. Amiodarone (0.5 mM) had no effect on basal 14CO2 formation or 32PO4 incorporation into phospholipids but significantly inhibited TSH, phorbol ester, and carbachol stimulation of these parameters. It also inhibited cAMP stimulation by TSH. Inhibition of TSH-stimulated [14C]glucose oxidation was also obtained with another iodide-containing compound, iopanoic acid (0.5 mM), but not with iothalamate (up to 10 mM). Inhibition by amiodarone was still present, but to a lesser extent, when it was added at the same time as the agonist. Inhibition of stimulated [14C]glucose oxidation persisted even after the slices were incubated without amiodarone for 6 h. Inhibition by amiodarone, in contrast to that by inorganic iodide, was not prevented by 1 mM methimazole added at the same time as amiodarone. These results indicate that the inhibitory effects of amiodarone on thyroid function are not due to dissociation of iodide from the molecule.

Amiodarone↗

PubMed1981

Competition between serum albumin and soluble fraction of liver for binding of warfarin and other drugs.

The binding of Warfarin by human serum albumin (HSA) and subcellular fractions from rat liver was investigated to evaluate the roles of such interactions in the pharmacokinetic properties of the anticoagulant. In vitro intracellular distribution studies showed that Warfarin was bound primarily by the soluble fraction of rat liver. Equilibrium dialysis studies were carried out to test the hypothesis that the hepatic extraction of Warfarin and drug interactions between Warfarin and other drugs involved competition between albumin and the soluble fraction of liver. A three compartment dialysis cell was designed and constructed for such studies. Three types of competitive binding interactions were identified. Iopanoic acid displaced Warfarin from HSA resulting in increased Warfarin in the protein-free compartment and in the compartment containing the soluble fraction. On the other hand, tolbutamide displaced Warfarin from HSA to the liver soluble fraction with relatively little effect on unbound anticoagulant. Sulfinpyrazone produced a third type of interaction characterized by displacement of Warfarin from HSA with an increase in the concentration of unbound drug. It was concluded that competitive binding between albumin and soluble liver proteins, is important in the hepatic uptake of Warfarin. The three compartment dialysis cells may be useful to simulate the distribution of drugs and drug combinations between non-dialyzable macromolecules.

Animals↗

PubMed1994

The presence of higher levels of thyroglobulin, but not thyroid autoantibodies, in the thyroid vein in Graves' disease.

To investigate the possible major source of thyroid autoantibodies production, blood samples were obtained from thyroid vein, jugular vein and peripheral vein during subtotal thyroidectomy in 12 patients with Graves' disease (11F, 1M; age 16-39 yr). Among them, 7 were treated preoperatively by methimazole, 4 by iopanoic acid and 1 by propranolol. All blood samples were assayed for thyroglobulin (Tg), thyrotropin binding inhibition immunoglobulin (TBII), antithyroglobulin antibody (TgAb) and antimicrosomal antibody (McAb). Tg, a native product of thyroid gland, was markedly elevated in the thyroid veins, over 4 to 6 folds that of jugular veins or peripheral veins. However, the level of thyroid autoantibodies including TBII, TgAb and McAb in the thyroid veins were not significantly different from that in the jugular or peripheral veins. Our preliminary data suggest that it is thyroglobulin, and not thyroid antibodies that is present at higher level in the thyroid vein than the periphery.

Adolescent↗

PubMed1990

Evidence for the role of thyroxine as a hormone in the physiology of a lizard.

In vivo effects of thyroxine (T4) and triiodothyronine (T3) were studied in male lizards. T4 or T3 (0.5 to 2 nmol) was administered per day over 10 days to surgically thyroidectomized male lizards (35 +/- 2.0 g) and the responses were measured in terms of scale shedding, whole body oxygen consumption (OC), and testicular weight. T3 was more effective in stimulating OC as compared to T4. T4 accelerated scale shedding to a greater extent as compared to T3. T4 was more effective than T3 in restoring the decline in the gonadal weight of thyroidectomized animals. Effect of inhibition of peripheral conversion of T4----T3 by iopanoic acid (IOP) was studied on the above response parameters. IOP at both dose levels inhibited extrathyroidal conversion of T4----T3. The T4-stimulated increase in OC of IOP-treated animals was suppressed, clearly indicating that the T4 effect could be attributed to its conversion to T3. But in these same animals, IOP failed to inhibit T4-stimulated scale shedding and gonadal weight. As the proportion of T4 converted to T3 decreased as a result of IOP treatment, the effectiveness of T4 increased in terms of scale shedding and restoration of gonadal weight. From these studies it appears that all effects of T4 in lizards need not necessarily be mediated via conversion to T3.

Animals↗

PubMed2004

Expression of type II iodothyronine deiodinase marks the time that a tissue responds to thyroid hormone-induced metamorphosis in Xenopus laevis.

The thyroid gland synthesizes thyroxine (T4), which passes through the larval tadpole's circulatory system. The enzyme type II iodothyronine deiodinase (D2) converts thyroxine (T4) to the active hormone 3,5,3'-triiodothyronine (T3) in peripheral tissues. An early response to thyroid hormone (TH) in the Xenopus laevis tadpole is the stimulation of cell division in cells that line the brain ventricles, the lumen of the spinal cord, and the limb buds. These cells express constitutively high levels of D2 mRNA. Exogenous T4 induces early DNA synthesis in brain, spinal cord, and limb buds as efficiently as T3. The deiodinase inhibitor iopanoic acid blocks T4- but not T3-induced cell division. At metamorphic climax, both TH-induced cell division and D2 expression decrease in the brain. Then D2 expression appears in late-responding tissues including the anterior pituitary, the intestine, and the tail where cell division is reduced or absent. Therefore, constitutive expression of D2 occurs in the earliest target tissues of TH that will grow and differentiate, while TH-induced expression of D2 takes place in late-responding tissues that will remodel or die. This pattern of constitutive and induced D2 expression contributes to the timing of metamorphic changes in these tissues.

Animals↗

PubMed1982

Effect of blocking T4-monodeiodination on hatching in chickens.

Chick embryos were injected with iopanoic acid (IOP) on either day 17 or 18 of incubation, and radioimmunoassays of triiodothyronine (T3) and thyroxine (T4) in serum and thyroid glands were performed from day 19 on through pipping and hatching and 1 day after hatching. The IOP was able to block T4 to T3 conversion in chick embryos from day 19 of incubation. Blocking T4 conversion did not delay hatching significantly, nor did it affect embryonic mortality significantly. Yolk sac retraction was not affected at hatching. A rise in serum reverse T3 (rT3) and T4 was observed after IOP administration. The rise in T4 could not be explained solely by a decreased T4 conversion. The results indicated that peripheral monodeiodination occurs in the late chick embryo.

Animals↗

PubMed1996

Inhibition of 5'DI and 5'DII L-tiroxine (T4) monodeiodinases. Effect on the hypothalamo-pituitary ovarian axis in adult hypothyroid rats treated with T4.

Hypothyroid female rats were treated with T4 and their 5'DI and 5'DII deiodinases were inhibited by PTU and IOP administration to determine whether the effect of T3 on reproductive function is a primary event at hypothalamo-pituitary levels or ovarian levels. Hypothyroid adult female rats were divided into four groups: Hypothyroid without treatment (H); hypothyroid treated with T4 (H-T4); hypothyroid treated with T4 plus propylthiouracil (H-T4-PTU), and hypothyroid treated with T4 plus iopanoic acid (H-T4-IOP). A group of euthyroid rats (E) was included as control. Estrous cycle, ovarian histological changes and serum estradiol and gonadotropin levels (basal and after GnRH) were searched in all groups. In view of our results and since sexual cycles and puberal pattern in gonadotropin secretion were restored after all treatments we can suggest: That T4 could have an intrinsic effect on reproductive function in adult hypothyroid female rats or that another compensatory T3 mechanism unaffected by IOP could exist. The present report points out that the effect of T3 on reproductive function could be a primary event at hypothalamopituitary levels although an effect at ovarian levels could not be excluded.

Animals↗

PubMed1989

Thyroid hormone regulation of hypothalamic immunoreactive thyrotropin.

Immunoreactive TSH (IR-TSH) has been identified in the hypothalamus and other brain areas in intact and hypophysectomized rats. To determine if thyroid hormones regulate IR-TSH in the rat brain, the effects of T3 and T4 on pituitary and hypothalamic IR-TSH content were studied in intact and hypophysectomized rats. Female rats received daily injections of T3 (0.1, 1.0, or 10 micrograms/100 g BW) or T4 (0.5, 2.5, or 5.0 micrograms/100 g BW) for 7 days. The chronic administration of T3 and T4 decreased the plasma concentration and pituitary content of IR-TSH in a dose-dependent manner. In intact rats, the administration of T3 did not affect the content of IR-TSH in the median eminence, ventral hypothalamus, or dorsal hypothalamus. In contrast, administration of T4 significantly increased the content of IR-TSH in the median eminence and ventral hypothalamus in a dose-dependent manner. Similarly, in hypophysectomized rats daily administration of T4 resulted in a dose-dependent increase in the concentration of IR-TSH in the median eminence and ventral hypothalamus. In hypophysectomized rats infusion of colchicine into the lateral ventricle, which blocks axonal transport, decreased the content of IR-TSH in the median eminence (631 +/- 59 vs. 439 +/- 36 microU/mg), increased the content of IR-TSH in the ventral hypothalamus (45 +/- 5 vs. 87 +/- 10 microU/mg), and blocked the T4-induced increase in IR-TSH in the median eminence. In intact rats, administration of iopanoic acid, which blocks the conversion of T4 to T3, decreased the content of IR-TSH in the median eminence (688 +/- 44 vs. 450 +/- 38 microU/mg) and ventral hypothalamus (103 +/- 16 vs. 70 +/- 5 microU/mg) and blocked the T4-induced increase in IR-TSH in the median eminence (1025 +/- 82 vs. 644 +/- 62 microU/mg) and ventral hypothalamus (229 +/- 23 vs. 117 +/- 11 microU/mg). These data indicate that TSH content in the median eminence and ventral hypothalamus is regulated by a thyroid hormone-sensitive mechanism which requires the local monodeiodination of T4 to T3. In addition, the effect of colchicine on the IR-TSH content in the median eminence and the T4-induced increase in brain IR-TSH are consistent with previous reports demonstrating that hypothalamic IR-TSH is regulated independently of pituitary and serum TSH.

Animals↗