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PubMedDate not supplied

Radiographic appearance of the nonabsorbed (unconjugated) and conjugated sodium tyropanoate (Bilopaque) in the bowel.

A series of abdominal radiographs were taken in eight normal volunteers after the ingestion of sodium tyropanoate (Bilopaque). These showed nonabsorbed sodium tyropanoate to have a granular appearance, while the conjugated form had a smooth homogeneous appearance. The appearance of conjugated sodium tyropanoate in the bowel has the same diagnostic significance as conjugated iopanoic acid in the presence of a nonvisualized gallbladder. It indicates that the contrast material has passed through the hepatic ductal system and that there has been an opportunity for the gallbladder to opacify.

Adult↗
PubMed2006

Comparison of enhancing effects of different goitrogen treatments in combination with beta-estradiol-3-benzoate for establishing a rat two-stage thyroid carcinogenesis model to detect modifying effects of estrogenic compounds.

With the aim of establishing a sensitive model for the detection of weak effects of endocrine disrupting chemicals on thyroid carcinogenesis, thyrotrophic and tumor-promoting influences of beta-estradiol-3-benzoate (EB) in combination with representative antithyroidal agents (goitrogens), sulfadimethoxine (SDM), propylthiouracil (PTU), potassium perchlorate (PPC), iopanoic acid (IOP) or an iodine-deficient diet were evaluated in a short-term (7-day) experiment without N-bis(2-hydroxypropyl)nitrosamine (DHPN) initiation and a long-term (30-week) experiment with DHPN initiation in ovariectomized F344 rats. In the short-term experiment, the most remarkable thyrotrophic effects were found in the PTU-treated group, followed by the SDM and PPC cases. EB treatment alone caused slight increases in thyroidal weights but no apparent morphological changes. Concomitant treatment with EB and antithyroidal agents enhanced the changes in thyroid weights, histopathological findings and/or serum thyroid hormone levels in the SDM (30 and 100 p.p.m), PTU (5 and 30 p.p.m) and PPC (100 p.p.m), IOP (30 and 100 mg/kg) or iodine-deficient diet groups. In the long-term experiment after DHPN initiation, EB alone slightly increased small numbers of animals with follicular hyperplasias, adenomas and adenocarcinomas. Simultaneous treatment with antithyroidal chemicals was associated with an increase in the incidences of focal hyperplasias, adenomas and/or adenocarcinomas. The enhancement was most remarkable with PTU (5 p.p.m), followed by PTU (2 p.p.m), SDM (100 p.p.m) and PPC (100 p.p.m). The results showed that EB has only a marginal promoting effect on DHPN-induced rat thyroid carcinogenesis and that antithyroidal chemicals, particularly PTU, are effective as co-promoting agents.

Animals↗
PubMedDate not supplied

The effect of various drugs on adenosine triphosphate content and histamine release from rat peritoneal cell suspensions rich in mast cells.

1. Iopanoic acid and iophenoxic acid were potent inhibitors of compound 48/80-induced histamine release from rat peritoneal cell suspensions rich in mast cells and caused a parallel dose-related reduction in ATP content of these cells. 2. Lignocaine was less potent and ouabain and probenecid were ineffective in inhibiting histamine release and reducing cellular ATP content. 3. Various drugs can inhibit 48/80-induced histamine release from rat peritoneal cells and this activity may result from depletion of cellular ATP. It is apparent that little structural specificity is required for activity in this cell system.

Adenosine Triphosphate↗
PubMed1988

Inhibition of pineal type-II 5'-deiodinase does not affect the nocturnal increase of N-acetyltransferase activity and melatonin content in either euthyroid or thyroidectomized rats.

The presence of type-II thyroxine 5'-deiodinase (5'-D) activity in rat pineal gland has been previously described. In the present paper, 5'-D activity, N-acetyltransferase (NAT) activity, and melatonin content were measured in the same rat pineal. Each of these constituents exhibits a nocturnal increase with peak values at 0100 h for melatonin (1.20 +/- 0.12 ng/gland) and at 0300 h for both 5'-D (39.5 +/- 11.9 fmol/gland/h) and NAT (8.38 +/- 1.04 nmol/gland/h) activities. In vivo treatment with iopanoic acid (IOP) completely prevented the nocturnal increase in 5'-D activity (14.1 +/- 2.6 fmol/gland/h at 0300 h) with no modification in either the NAT activity or melatonin content. Thyroidectomy greatly enhanced the 5'-D activity during the dark period (102.9 +/- 10.2 vs. 31.6 +/- 4.2 fmol/gland/h), reaching a peak at 0200 h; thyroidectomy, however, did not affect daytime pineal 5'-D activity (3.11 +/- 0.78 vs. 2.5 + 0.92 fmol/gland/h). Treatment of rats with IOP acid completely inhibited the pineal 5'-D activity in both control (7.86 +/- 0.88 fmol/gland/h) and thyroidectomized animals (2.24 +/- 1.10 fmol/gland/h) with no change in the melatonin content of the gland (1.21 +/- 0.32 vs. 0.99 +/- 0.18 ng/gland).

Acetyltransferases↗
PubMed1989

Cytosol components from human placenta and rat liver in iodothyronine 5- and 5'-deiodination.

Using either human placental microsomal 5-deiodinase as enzyme (5-DI) and thyroxine as substrate or rat liver (RL) microsomal 5'-deiodinase (5'DI) as enzyme and reverse [(3'- or 5'-)-125I]triiodo-L-thyronine ([125I]rT3) as substrate, activation of 5'-DI in the presence of NADPH was observed using either human placental or rat liver cytosolic components, but there was no activation of 5-DI. Both could be activated by DTT, with higher concentrations being required for 5-DI than for 5'-DI. Iopanoic acid, dicumarol, and sodium arsenite inhibited 5'-DI and 5-DI activated by DTT. In the presence of DTT, 1 mM 6-propyl-2-thiouracil had no effect on 5-DI but inhibited 5'DI. Thus, human placental and rat liver cytosolic components are interchangeable in activating hepatic 5'-DI in the presence of NADPH. However, if an endogenous cofactor system involved in the activation of human placental 5-DI exists, it probably differs from the activator of liver 5'-DI.

Animals↗
PubMed1981

Single-visit oral cholecystography for inpatients.

A new one-day medication schedule for single-visit oral cholecystography is described, using both Telepaque (iopanoic acid) tablets and Oragrafin Sodium (sodium ipodate) capsules. A definitive report is rendered at the first sitting; no repeat studies are performed. Preliminary results in 45 patients demonstrate the accuracy of this technique. One-day medication makes single-visit oral cholecystography suitable for hospitalized patients.

Cholecystography↗
PubMed2002

Thyroid status, but not insulin status, affects expression of avian uncoupling protein mRNA in chicken.

The aim of this study was to investigate the hormonal regulation of the avian homolog of mammalian uncoupling protein (avUCP) by studying the impact of thyroid hormones and insulin on avUCP mRNA expression in chickens (Gallus gallus). For 3 wk, chicks received either a standard diet (control group), or a standard diet supplemented with triiodothyronine (T(3); T3 group) or with the thyroid gland inhibitor methimazole (MMI group). A fourth group received injections of the deiodinase inhibitor iopanoic acid (IOP group). During the 4th wk of age, all animals received two daily injections of either human insulin or saline solution. The results indicate a twofold overexpression of avUCP mRNA in gastrocnemius muscle of T3 birds and a clear downregulation (-74%) in MMI chickens compared with control chickens. Insulin injections had no significant effect on avUCP mRNA expression in chickens. This study describes for the first time induction of avUCP mRNA expression by the thermogenic hormone T(3) in chickens and supports a possible involvement of avUCP in avian thermogenesis.

Animals↗
PubMed1987

Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation.

We have examined the activity of three lipogenic enzymes [malic enzyme (ME), glucose-6-phosphate dehydrogenase (G-6-PD), and acetyl coenzyme A (CoA) carboxylase], the activity of the mitochondrial FAD-dependent alpha-glycerolphosphate dehydrogenase (alpha-GPD), and the mitochondrial concentration of uncoupling protein (UCP) in brown adipose tissue (BAT) of euthyroid and hypothyroid rats, both at room temperature and in response to acute cold stress. These enzymes and UCP are important for the thermogenic response of BAT in adaptation to cold. The basal level of the lipogenic enzymes was normal or slightly elevated in hypothyroid rats maintained at 23 degrees C, but the levels of alpha-GPD and UCP were markedly reduced. Forty-eight hours at 4 degrees C resulted in an increase in the activity of G-6-PD, acetyl-CoA carboxylase, and alpha-GPD and in the concentration of UCP both in euthyroid and hypothyroid animals, but the levels reached were invariably less in hypothyroid animals, indicating that thyroid hormone is necessary for a full metabolic response of BAT under maximal demands. Of all variables measured, the most affected was UCP (only one-fifth of the response of euthyroid rats to cold) followed by alpha-GPD (approximately 50% the euthyroid response). The administration of replacement doses of triiodothyronine (T3) to hypothyroid rats for 5-7 days did not normalize any of the BAT responses, whereas the replacement of thyroxine (T4) for only 2 days sufficed to normalize them all. This effect of T4 was abolished by preventing its conversion to T3 with iopanoic acid.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue, Brown↗
PubMed1984

The role of thyroid hormone deiodination in the regulation of hypothalamo-pituitary function.

There is extensive deiodinative metabolism of thyroxine (T4) in thyroid hormone target organs, including the pituitary and brain. In both rat and man, most of the 3,3',5-triiodothyronine (T3) in the body is produced outside the thyroid gland by deiodination of T4. T3 is the principal active form of thyroid hormone within cells. In the rat, there are at least three enzymatic iodothyronine-deiodinating pathways which can be distinguished by kinetics and substrate and inhibitor specificities. Two of these (types I and II) can convert T4 to T3. The third pathway (type III) converts T4 to the inactive reverse-T3 and T3 to an inactive diiodothyronine. Both the anterior pituitary and the brain produce most of their intracellular T3 locally, by the type-II pathway. Type-III activity is present throughout the brain, but not in the anterior pituitary. Studies in the rat, using the deiodination inhibitor iopanoic acid, show that the capacities of T4 to inhibit thyrotropin release and stimulate growth hormone synthesis require conversion of T4 to T3 in the pituitary. Studies in man strongly suggest that the same is true in the human adenohypophysis, and a syndrome in man of a deficiency in this process possibly exists. The hypothalamus exhibits some responses to thyroid hormone, including changes in somatostatin and substance P content and changes in activities of type-II and III deiodination. The mechanism(s) of action of thyroid hormone in the hypothalamus, and in the brain in general, are not yet well understood.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1978

Iodothyronine metabolism in rat liver homogenates.

To investigate mechanisms of extrathyroidal thyroid hormone metabolism, conversion of thyroxine (T(4)) to 3,5,3'-triiodothyronine (T(3)) and degradation of 3,3',5'-triiodothyronine (rT(3)) were studied in rat liver homogenates. Both reactions were enzymatic. For conversion of T(4) to T(3), the K(m) of T(4) was 7.7 muM, and the V(max) was 0.13 pmol T(3)/min per mg protein. For rT(3) degradation, the K(m) of rT(3) was 7.5 nM, and the V(max) was 0.36 pmol rT(3)/min per mg protein. Production of rT(3) or degradation of T(4) or T(3) was not detected under the conditions employed. rT(3) was a potent competitive inhibitor of T(4) to T(3) conversion with a K(i) of 4.5 nM; 3,3'-diiodothyronine was a less potent inhibitor of this reaction. T(4) was a competitive inhibitor of rT(3) degradation with a K(i) of 10.2 muM. Agents which inhibited both reactions included propylthiouracil, which appeared to be an allosteric inhibitor, 2,4-dinitrophenol, and iopanoic acid. Sodium diatrizoate had a weak inhibitory effect. No inhibition was found with alpha-methylparatyrosine, Fe(+2), Fe(+3), reduced glutathione, beta-hydroxybutyrate, or oleic acid. Fasting resulted in inhibition of T(4) to T(3) conversion and of rT(3) degradation by rat liver homogenates which was reversible after refeeding. Serum T(4), T(3), and thyrotropin concentrations fell during fasting, with no decrease in serum protein binding as assessed by a T(3)-charcoal uptake. There was no consistent change in serum rT(3) concentrations. Dexamethasone had no effect in vitro. In vivo dexamethasone administration resulted in elevated serum rT(3) concentrations after 1 day, and after 5 days, in inhibition of T(4) to T(3) conversion and rT(3) degradation without altering serum T(4), T(3), or thyrotropin concentrations. Endotoxin treatment had no effect of iodothyronine metabolism in liver homogenates. In kidney homogenates the reaction rates and response to propylthiouracil in vitro were similar to those in liver. No significant T(4) to T(3) conversion or rT(3) production or degradation could be detected in other tissues. These data suggest that one iodothyronine 5'-deiodinase is responsible for both T(4) to T(3) conversion and rT(3) degradation in liver and, perhaps, in kidney. Alterations in serum T(3) and rT(3) concentrations induced by drugs and disease states may result from decreases in both T(3) production and rT(3) degradation consequent to inhibition of a single reaction in the pathways of iodothyronine metabolism.

Animals↗
PubMed1982

Comparison of iodothyronine 5'-deiodinase and other thyroid-hormone-dependent enzyme activities in the cerebral cortex of hypothyroid neonatal rat. Evidence for adaptation to hypothyroidism.

Recent studies have shown that approximately 75% of the nuclear 3,5,3'-triiodothyronine (T(3)) present in adult rat cerebral cortex (Cx) derives from 5'-deiodination of thyroxine (T(4)) within this tissue. The activity of iodothyronine 5'-deiodinase (I 5'D), the enzyme catalyzing T(4) to T(3) conversion, increases rapidly after thyroidectomy, suggesting that this could be a compensatory response to hypothyroxinemia. To evaluate this possibility during the period of central nervous system maturation, we studied several thyroid hormone-responsive enzymes (aspartic transaminase [AT], succinic dehydrogenase [S.D.], and Na/K ATPase) in the Cx of 2-, 3-, and 4-wk-old rats. The rats were made congenitally hypothyroid by placing 1, 2, 5, and 20 mg methimazole (MMI) in 100 ml of the mothers' drinking water from day 16 of gestation throughout the nursing period and to the litters after weaning. In addition, serum thyroid hormones, I 5'D, and, in some experiments, in vivo T(4) to T(3) conversion in Cx were measured in the same pups. Serum T(4) concentrations varied from <1 to 40 ng/ml and were generally inversely related to maternal MMI dose. Serum T(3) was less affected by MMI than was T(4). At 2 wk, decreases in AT, S.D., and ATPase were present in the 20-mg-MMI group but not in the 5-mg-MMI pups despite low serum T(4) (<10 ng/ml) in the latter. At 3 and 4 wk, both 5- and 20-mg-MMI groups had significant reductions in these cortical enzymes despite a normal serum T(3) in the 5-mg-MMI rats. Cortical I 5'D activity was 10-fold the control value in 5- and 20-mg-MMI animals at 2 wk but increased only three- to fivefold at 3 and 4 wk. I 5'D correlated inversely with serum T(4) (r >/= 0.96) at all ages, but the less marked elevation of this enzyme in 3- and 4-wk-old pups was not accompanied by an increase in serum T(4). Serum T(3) increased or remained the same between 2 and 3 wk. These results suggested that the 10-fold increase in I 5'D at 2 wk protected the 5-mg-MMI group from tissue hypothyroidism, but that the three- to fivefold increase at 3 and 4 wk could not. Injection of approximately 250 ng T(4)/100 g body weight to 2-wk-old, 20-mg-MMI pups (one-sixth the normal T(4) production rate) led to both a 1.8-ng/g cortical tissue increment in cortical T(3) and a significant increase in AT at 24 h, compared with a 0.38-ng/g cortical tissue T(3) increment and no change in AT in euthyroid controls. The larger increment in T(3) of the 20-mg-MMI pups was due in great part to increased fractional T(4) to T(3) conversion. Although the latter resulted in greater serum T(3) concentrations, three-fourths of the newly formed T(3) in the cortex was generated in situ, and it was blocked by iopanoic acid as was the increase in AT. We conclude that 70-80% of the T(3) in the Cx of the neonatal rat is produced locally. Serum T(4) appears to serve both as a precursor for T(3) and as a critical signal for increases in cortical I 5'D. The increased I 5'D can result in normal or near-normal cerebrocortical T(3) concentrations despite marked reductions in serum T(4). This mechanism seems to be particularly effective around 2 wk of age when many thyroid-hormone-dependent maturational changes occur in the rat Cx.

Adenosine Triphosphatases↗
PubMed1985

Characteristics of thyroxine 5'-deiodination in cultured human placental cells. Regulation by iodothyronines.

Human and rat placental homogenates convert L-thyroxine (T4) to 3,5,3'-L-triiodothyronine (T3) via a pathway termed type II iodothyronine deiodination. To study regulation of this pathway, cell dispersions were prepared from human placental chorionic-decidual membrane. Dispersed cells deiodinated T4 and 3,3',5'-triiodothyronine (rT3), but not T3, at the 5' position. The reaction was only slightly inhibited by 1 mM 6-n-propylthiouracil, enhanced by dithiothreitol, and substantially inhibited by 50 nM iopanoic acid. Incubation of the cells in thyroid hormone-depleted medium induced a near doubling of T4 5'-deiodination in 36-48 h, with a significant rise seen as early as 12 h. Addition of T4, rT3, or T3 to hormone-depleted medium impaired the rise in type II deiodination in a dose-dependent fashion. T4 and rT3 were equipotent in this regard, and T3 was 2-3 times less potent. T4 was effective in physiological concentrations, 6.5-13 nM in medium containing 10% calf serum, and the effect of T4 was not due to its conversion to either T3 or rT3. In cells with deiodinase activity raised by 48 h incubation in thyroid hormone-depleted medium, addition of T4, T3, or rT3 reversed the increase in 8-24 h. Secretion of prolactin and beta hCG by the dispersed cells was not substantially affected by thyroid hormone deprivation. The increase in type II deiodination during thyroid hormone deprivation appears to depend on a signal from the thyroxine molecule, per se, and could potentially defend intracellular, and/or circulating, T3 pools in pathological states of mild-to-moderate hypothyroxinemia.

Cell Separation↗
PubMed1985

Subcellular localization of thyroxine 5'-deiodinase activity in bovine anterior pituitary.

Bovine anterior pituitary glands were fractionated by differential centrifugation. T4 5'-monodeiodination to T3 was found predominantly in microsomal fractions (M2; 105,000 . g pellet) enriched in glucose-6-phosphatase and 5'-nucleotidase activities. T4 5'-deiodinase activity in M2 fraction was 85.2 fmol T3/min X mg protein and represented an 8.5-fold enrichment over homogenate specific activity (10.6 fmol T3/min . mg protein). Further subcellular localization of the T4 5'-deiodinase was effected by discontinuous sucrose density gradient centrifugation. Maximum T4 5'-deiodinase activity was found in fraction P5 at the interface of densities 1.18/1.20 (200 fmol T3/min . mg protein) and correlated with the profile of glucose-6-phosphatase and not with that of 5'-nucleotidase, the maximum activity of which was recovered in fraction P1 at the interface of densities 1.03/1.12. Electron microscopic examination of the fractions confirmed that P5 contained in excess of 90% rough membranes in contrast to 10% or less in P1. Characterization of T4 5'-deiodinase activity was carried out in M2 preparations. The reaction was thiol dependent, requiring the presence of 50 mM dithiothreitol or more (Km, 38 mM), with a maximum velocity of 55-150 fmol T3/min . mg protein (n = 8). Enzyme activity was substrate dependent, with a Km for T4 between 35-70 nM. 5'-Monodeiodination of T4 was abolished by heating to 70 C for 30 min and was unaffected by EDTA. Propylthiouracil and methimazole did not inhibit T3 generation. Iopanoic acid, on the other hand, was a competitive inhibitor of the 5'-monodeiodination reaction, abolishing T3 production in a dose-dependent manner with a Ki of 3 microM. These data indicate that the bovine anterior pituitary contains significant T4 5'-deiodinase activity, which shares many properties of the type II 5'-deiodinase of the rat. Bovine anterior pituitary T4 5'-deiodinase appears to be predominantly localized in the rough endoplasmic reticulum.

Animals↗
PubMed1988

Thyroxine 5'-deiodinase activity in pineal gland and frontal cortex: nighttime increase and the effect of either continuous light exposure or superior cervical ganglionectomy.

Type II T4 5'-deiodinase (5'-D) activity was studied in pineal gland, frontal cortex, and anterior pituitary of male rats. Enzymatic activity was determined by the release of 125I using [3',5'-125I]T4 as substrate. Daytime levels of 5'-D activity were maximal for anterior pituitary (346.2 +/- 142.5 fmol 125I released/mg protein.h), followed by pineal gland (61.5 +/- 8.7 fmol 125I released/mg protein.h) and frontal cortex (3.1 +/- 0.5 fmol 125I released/mg protein.h). Twenty-four-hour fluctuations of 5'-D activity were apparent in the pineal gland and cortex. For pineal, peak 5'-D activity (43.4 +/- 11.4 fmol 125I released/gland.h) occurred at 0100 h, with values at this time being 8-fold greater than basal daytime levels. Superior cervical ganglionectomy (SCGX) or exposure to continuous light (LL) completely abolished the nocturnal rise of 5'-D activity. Treatment with iopanoic acid also inhibited 5'-D activity in pineal (32.1 +/- 3.5 vs. 18.8 +/- 1.7 fmol 125I released/gland.h) without influencing either the N-acetyltransferase activity or the melatonin content. In cortex, peak 5'-D activity occurred at 0500 h (5.3 +/- 0.4 fmol 125I released/mg protein.h), with values at this time being 1.5-fold greater than basal daytime levels. SCGX moderately depressed enzymatic activity, while LL exposure strikingly enhanced the nocturnal increase (11.7 +/- 1.1 vs. 19.3 +/- 2.4 fmol 125I released/mg protein.h at 0300 h). 5'-D activity exhibited no 24-h fluctuation in the anterior pituitary gland, and neither SCGX nor LL exposure affected enzyme levels in this tissue. Our data demonstrate the existence of a 24-h rhythm of type II T4 5'-D activity in pineal gland and cortex, with peak levels occurring at night; in pineal, the sympathetic neural input is indispensable for the rhythm, since SCGX prevented it. In cortex, the apparent paradoxical effect of LL and SCGX on 5'-D activity indicates that other mechanisms are involved in its regulation.

Animals↗
PubMed1989

Ligand-induced inactivation of type I iodothyronine 5'-deiodinase: protection by propylthiouracil in vivo and reversibility in vitro.

The inactivation of the phenolic ring deiodinases by natural substrates and iodinated contrast agents such as iopanoic acid (IOP) is a principal mechanism regulating the peripheral metabolism of thyroid hormones. The present studies were designed to investigate the cellular and biochemical mechanisms mediating this effect on type I 5'-deiodinase (5'DI) in rat liver and kidney. We reasoned that if inactivation requires the direct interaction of ligand (e.g. IOP) with 5'DI, then this effect should be blocked by a prior injection of 6n-propyl-2-thiouracil (PTU), which binds to an essential sulfhydryl group at the enzyme's active site and inhibits catalytic cycling. Experiments were performed using liver and kidney microsomes prepared from male rats injected 2.5 or 6 h earlier with various combinations of PTU, IOP, and/or vehicle. In initial studies, conditions were defined whereby active 5'DI could be regenerated in vitro from PTU-injected animals. This involved the treatment of microsomes with 50 mM dithiothreitol, pH 7.0, before assay. After this reductive treatment, 5'DI activity in both liver and kidney microsomes from rats previously injected with PTU, or the combination of PTU followed 30 min later by IOP, was equivalent to that in vehicle-injected control animals, whereas activity was decreased 60% in microsomes from animals injected with only IOP. This demonstrates that PTU protects 5'DI against ligand-induced inactivation, suggesting that this process is initiated by substrate binding to the enzyme's active site. In other experiments, liver microsomes from IOP-injected animals were pretreated with 100 mM dithiothreitol, pH 9.0, then washed, and 5'DI activity was determined. Under these stringent reducing conditions, 5'DI activity was completely recovered in microsomes from rats injected with IOP 2.5 h earlier, but only partially recovered 6 h after the IOP injection. Thus, ligand-induced inactivation of 5'DI may involve initially a reversible oxidation of the enzyme, followed by its irreversible inactivation.

Animals↗
PubMed1997

The type 2 and type 3 iodothyronine deiodinases play important roles in coordinating development in Rana catesbeiana tadpoles.

In developing Rana catesbeiana tadpoles, the timing of the thyroid hormone (TH)-dependent metamorphic responses varies markedly among tissues. Yet at any one time these tissues are exposed to the same plasma concentration of TH, suggesting that TH action is regulated in part at the level of the peripheral tissues. A major factor in TH action is the intracellular level of the active TH, T3. This level is dependent not only on the plasma concentration of TH (mostly T4) but also on the intracellular activities of the type 2 5'-deiodinase (D2) and the type 3 5-deiodinase (D3), which are responsible, respectively, for generating and degrading T3. (D1 is not present in this species.) To determine whether differential expression of D2 and D3 among tissues could be a significant factor in the coordination of metamorphic events, the ontogenic profiles of the two enzyme activities and corresponding messenger RNA levels in most tissues of R. catesbeiana tadpoles have been documented. The profiles of D2 expression in tail, hindlimb, forelimb, intestine, skin, and eye differed markedly at both activity and messenger RNA levels, but it was notable that expression was invariably highest in a given tissue at the time of its major metamorphic change. D2 expression was very low in brain and heart and did not vary during development. D2 was not expressed in liver, kidney, or red blood cells. With the exception of red blood cells, D3 expression was detected in all tissues studied. Furthermore, it was evident that in tissues that expressed both deiodinase genes, the two expression profiles were comparable, indicating a potential for tight control of intracellular T3 levels. Direct evidence of the importance of the intracellular conversion of T4 to T3 for TH-dependent metamorphic events was obtained in tadpoles in which endogenous TH synthesis was blocked with methimazole, and the activities of D2 and D3 were inhibited by iopanoic acid. This treatment inhibited metamorphosis. The inhibition could be overcome by the concomitant administration of replacement levels of T3, but not T4. These results strongly support the view that coordinated development in amphibia depends in part on the tissue-specific expression patterns of the D2 and D3 genes, which ensure that the requisite level of intracellular T3 is attained in a given tissue, regardless of the current level of circulating TH, at the appropriate stage of metamorphosis.

Animals↗
PubMed2000

3,5-diiodo-L-thyronine regulates glucose-6-phosphate dehydrogenase activity in the rat.

Thyroid hormones influence the activity of lipogenic enzymes such as malic enzyme (ME) and glucose-6-phosphate dehydrogenase (G6PD). The effect of T3 on ME is exerted at the transcriptional level, but it is unclear if its effect on G6PD is also nuclear mediated. Furthermore, other iodothyronines that have been shown to possess biological activity (such as diiodothyronines) could contribute to this enzyme's regulation. In this study the effects of 3,5-diiodothyronine (T2) on the aforementioned enzymes were examined and compared with those of T3. Rats made hypothyroid by propylthiouracil and iopanoic acid treatment were used throughout. Enzyme activities were determined spectrophotometrically, and G6PD messenger RNA (mRNA) expression was analyzed by Northern blotting using a human G6PD complementary DNA probe. Injections of T2 to hypothyroid animals significantly enhanced the activity of both enzymes. The effect of T2 on ME was nuclear mediated and mimicked the effect of T3. The effects of T2 and T3 on G6PD differed. Injection of T3 into hypothyroid rats induced an increase in both enzyme activity and G6PD mRNA expression, indicating a nuclear-mediated effect. The effect of T2 on G6PD activity, on the other hand, was not nuclear mediated. The injection of T2 into hypothyroid animals did not change G6PD mRNA expression, and the strong increase in the enzyme's activity (from +70% to +300%) was unaffected by simultaneous injection of protein synthesis inhibitors. As the lowest dose of 1 microg T2/100 g BW affects G6PD activity 3-5 times more than the same dose of T3, these data provide the first evidence that T2 is a factor capable of regulating G6PD activity.

Animals↗