| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLE |
1: In Vitro and in Vivo Evidence
Departments of Endocrinology and Metabolism, and Cardiology (W.M.C.J.), Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; and Department of Internal Medicine, Erasmus University Medical Center (E.K., T.J.V.), 3015 GE Rotterdam, The Netherlands
Address all correspondence and requests for reprints to: Dr. H. C. van Beeren, Department of Endocrinology and Metabolism, Academic Medical Center F5-171, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: h.c.vanbeeren{at}amc.uva.nl.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 (TR1) and TRß1 antagonist. Here we investigate whether Dron and/or its metabolite debutyldronedarone inhibit T3 binding to TR1 and TRß1 in vitro and whether dronedarone behaves similarly to amiodarone in vivo.
In vitro, Dron had a inhibitory effect of 14% on the binding of T3 to TR1, but not on TRß1. Desethylamiodarone inhibited T3 binding to TR1 and TRß1 equally. Debutyldronedarone inhibited T3 binding to TR1 by 77%, but to TRß1 by only 25%.
In vivo, AM increased plasma TSH and rT3, and decreased T3. Dron decreased T4 and T3, rT3 did not change, and TSH fell slightly. Plasma total cholesterol was increased by AM, but remained unchanged in Dron-treated animals. TRß1-dependent liver low density lipoprotein receptor protein and type 1 deiodinase activities decreased in AM-treated, but not in Dron-treated, animals. TR1-mediated lengthening of the QTc interval was present in both AM- and Dron-treated animals.
The in vitro and in vivo findings suggest that dronedarone via its metabolite debutyldronedarone acts as a TR1-selective inhibitor.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
SR 33589 B; Dron; Fig. 1
] is a new antiarrhythmic drug devoid of iodine, developed to replace the widely used, very potent, antiarrhythmic drug amiodarone (AM; Fig. 1), which releases pharmacological quantities of iodine during its biotransformation. Consequently, treatment with AM gives rise to iodine-induced hypothyroidism or thyrotoxicosis in approximately 15% of patients (1). Apart from the effect of iodine excess on the thyroid gland induced by AM, it profoundly affects extrathyroidal metabolism of thyroid hormones. AM decreases the 5'-deiodination of T4 into T3 in the liver mediated by inhibition of cellular T4 uptake. The main metabolite of AM, desethylamiodarone (DEA; Fig. 1), was found to inhibit the binding of T3 to its nuclear receptors. Indeed, AM treatment causes a dose-dependent decrease in the expression of several T3-dependent genes. For instance, the AM-induced increase in plasma low density lipoprotein (LDL) cholesterol is explained by a decrease in the hepatic expression of the LDL receptor gene at both the mRNA and protein levels (2, 3). Interestingly, the type of inhibition differs for 1- and ß1-thyroid hormone receptors (TR1 and TRß1, respectively). DEA is a competitive inhibitor of T3 binding to TR1 (4), whereas it is a noncompetitive inhibitor of T3 binding to TRß1 (5). Protein-protein binding studies with the hTRß1 and the coactivator glucocorticoid receptor interacting protein (GRIP-1) showed an inhibitory effect of DEA on the T3 dependent binding of the coactivator to TRß1 (6). This mechanism of action further supports the idea that DEA has a T3 antagonistic effect. It is thus of much interest to evaluate whether the new related drug, Dron, has the same effect as AM on extrathyroidal hormone metabolism and T3 receptor binding. Dron is now under active study intended to determine its usefulness in patients with cardiac arrhythmias (7). The aim of the present study was to investigate a putative inhibitory effect of Dron and its metabolite, debutyldronedarone (DBDron), on the binding of T3 to TR1 and TRß1. To this end we performed in vitro binding studies with expressed TR1 and TRß1 proteins and in vivo studies in rats where we concentrated on a number of postreceptor effects mediated by TR1 and TRß1. In both studies we compared the effect of Dron with that of AM.
|
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In vitro receptor binding assay
The chicken 1 (amino acids 1–408) and the human ß1 (amino acids 153–461) TRs were expressed in Escherichia coli, isolated as described previously (8, 9), and stored in incubation buffer [20 mM Tris-HCl, 0.25 mM sucrose, 1 mM EDTA, 50 mM NaCl, and 5% (vol/vol) glycerol, pH 7.6] containing 5 mM dithiothreitol (DTT) in liquid nitrogen. Receptor proteins were thawed on ice (20–25 µg protein/tube) and were incubated with [125I]T3 (10-11 M) for 30 min at 22 C in a shaking water bath in incubation buffer with 5 mM DTT, 0.025% Triton X-100, 0.05% BSA, and 1% ethanol (vol/vol). The total incubation volume was 0.5 ml. Reactions were stopped by chilling on ice water. Bound and unbound [125I]T3 were separated at 4 C using a small Sephadex G-25 medium column (bed volume, 2 ml; swollen in incubation buffer with 0.05% BSA) in a Pasteur pipette. Four 0.8-ml fractions, containing the bound hormone fraction, were collected using incubation buffer as eluent. Specific binding was determined by calculating the difference between the counts bound in the absence and presence of an excess (10-7 M) of nonradioactive T3. All incubations were performed in duplicate.
The potency of Dron, DBDron, and DEA to inhibit the binding of T3 to TR1 and TRß1 was tested over a concentration range of 10–100 µM. The compounds solubilized in a stock solution of 10-2 M in ethanol were incubated with receptor proteins in the presence of [125I]T3 as described above. In all tubes the final ethanol concentration was 1% (vol/vol). Binding is expressed as the percentage of specifically bound [125I]T3 in the absence of the compounds. In each experiment the effect on T3 binding to TR1 and TRß1 was assayed simultaneously.
Scatchard analyses were performed with DBDron to investigate the type of inhibition. TR1 or TRß1 proteins in the presence of [125I]T3 were incubated with increasing amounts of nonradioactive T3 (1 x 10-10 to 33 x 10-10 M) in the absence or presence of DBDron (0, 25, and 50 µM). Changes in maximum binding capacity (MBC) and Ka as a function of DBDron concentration were tested by one-way ANOVA.
Langmuir plots were prepared from the data of the Scatchard analyses. To delineate the type of inhibition, we analyzed the data by one-way ANOVA to determine whether the intercepts on the y-axis differed significantly among the various drug concentrations. Evidence for competitive inhibition is one intercept on the y-axis and dose-dependent increasing intercepts on the x-axis, whereas noncompetitive inhibition is characterized by one intercept on the x-axis and dose-dependent increasing intercepts on the y-axis.
In vivo studies
Male Wistar rats (220–260 g), housed under normal conditions with free access to standard laboratory chow and tap water, were divided into four groups (eight rats per group). They received water (controls), an aqueous suspension of 50 mg/kg body weight Dron (Dron50), 100 mg/kg body weight Dron (Dron100), or 100 mg/kg body weight AM (AM100) by gastric tube daily for 2 wk. Twenty-four hours after the last administration, electrocardiographs (ECGs) were made. During ECG recording, body temperature was kept constant (36.6–37.4 C) by a custom-made, water-heated, warming pad and was monitored by a rectal probe (Ellab, Roedovre, Denmark). Rats were kept under anesthesia and could freely breathe under 100% oxygen-supplemented air (0.2 liter/min) via a cone (density, 0.7 mm) 1 cm from their nose. AgCl-coated silver needles were used to record ECG (Einthoven lead I). Output signals were amplified by a custom-made amplifier, sampled at 1 kHz (Data Acquisition Card AT-MIO-16E-10, National Instruments, Austin, TX), band pass-filtered at 100 Hz-50 Hz direct current, and analyzed using AcqKnowlegde software version 3.2.6 (MP 100 Manager, Biopac Systems, Inc., Santa Barbara, CA). Thereafter, blood was collected by cardiac puncture, and plasma was stored at -20 C. The liver was removed and stored in liquid nitrogen. All animal experiments were approved by our local animal welfare committee.
Plasma assays
Plasma cholesterol and triglycerides were determined using a fully enzymatic dye method (Modular P analyzer, Roche Molecular Biochemicals, Mannheim, Germany). Quantification of plasma LDL cholesterol and high density lipoprotein (HDL) cholesterol were carried out by precipitation as described previously (3). Total T4, total T3, and rT3 were measured by in-house RIAs (10), using rat null plasma as diluent. Free T4 (FT4) and TSH were determined by Delfia fluoroimmunoassay (PerkinElmer, Wallac, Inc., Freiburg, Germany). FT4 and FT3 indexes were calculated as the product of the total T4 or total T3, respectively, and T3 resin uptake. The latter was determined using the Immulite chemiluminescent immunoassay T3 uptake kit (Diagnostic Products, Los Angeles, CA). All samples were measured within one run. Data are expressed as the mean ± SD. Differences between the thyroid hormone parameters were tested using t test; differences between the lipid parameters were tested by Mann-Whitney rank-sum test.
LDL-r protein expression and type 1 deiodinase (D1) activity in liver
Liver whole cell extracts were prepared in homogenization buffer [10 mM HEPES, 10% glycerol, 0.25 M sucrose, 25 mM KCl, 1 mM EDTA, 5 nM DTT, and protein inhibitor mix (Complete, Roche Molecular Biochemicals), pH 7.6]. Thirty-five micrograms of protein were applied to a 7.5% SDS-PAGE gel, transferred to a polyvinylidene difluoride membrane using a wet electroblotting apparatus, and probed with a specific LDL-r goat polyclonal antibody (diluted 1:1000). A polyclonal rabbit antigoat horseradish peroxidase-conjugated secondary antibody (DAKO Corp., Copenhagen, Denmark; diluted 1:3000) was used to reveal primary antibody binding using the Western Light kit and Lumi-Imager software (Roche Molecular Biochemicals). D1 activity in liver was measured as previously described (11).
Values are expressed as the mean ± SD. Differences were determined by t test.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 and TRß1 are presented in Fig. 2, A and B. Dron at 100 µM showed a slight, but significant, inhibition of 14 ± 3% (P < 0.01) of T3 binding to TR1, but no inhibition of the binding of T3 to TRß1. For the metabolites DEA and DBDron, a dose-dependent inhibition of T3 binding to both receptor isoforms was observed. DEA at 100 µM inhibited the binding of T3 to TR1 by 94 ± 3% (P < 0.01) and that to TRß1 by 82 ± 4% (P < 0.01) compared with that when no DEA was present. DBDron at 100 µM strongly inhibited the binding of T3 to TR1 by 77 ± 3% (P < 0.01) but that to the TRß1 by only 25 ± 4% (P < 0.01) compared with no DBDron (by Mann-Whitney nonparametric rank-sum test; values are mean ± SEM; n = 5). DEA concentrations causing 50% inhibition of T3 binding (IC50 values) were 30 ± 4 and 71 ± 3 µM for TR1 and TRß1, respectively (Table 1), in good accordance with earlier studies (4, 9). The IC50 values of DBDron were 59 ± 4 and 280 ± 30 µM (Table 1) for TR1 and TRß1 respectively.
|
|
1 are depicted in Fig. 3. The MBC of TR1 was not affected by DBDron (P = 0.21), but the affinity constant (Ka) of T3 binding was decreased in a dose-dependent manner (P < 0.01), as shown in Table 2. Langmuir analyses confirmed the competitive nature of the inhibition of binding of T3 to TR1 by DBDron. The intercept on the y-axis did not change from 0–50 µM DBDron (P = 0.25), whereas the intercept on the x-axis increased in a dose-dependent way (P < 0.03).
|
|
. The inhibitory effect of DBDron on TRß1, however, was too low to perform reliable kinetic studies. MBC values did not show a dose-dependent relation (P = 0.82) with the DBDron concentration, and the Ka values did not decrease dose-dependently (P = 0.34).
In vivo studies: rat plasma parameters
Body weights were similar in the four groups at baseline. In the Dron100 group two rats died before the end of the study due to breathing problems. The gain in body weight during the experiment was lower in the Dron- and AM-treated animals than in controls (Table 3).
|
).
Total plasma cholesterol was not affected in the Dron50 and Dron100 groups compared with controls, nor were LDL cholesterol and HDL cholesterol affected by Dron. However, total cholesterol, LDL cholesterol, and HDL cholesterol increased in the AM group (Table 3).
In vivo studies: postreceptor effects in rat heart and liver
Heart rate, expressed as beats per minute, was not different among the groups. However, QTc intervals showed a dose-dependent prolongation in both Dron- and AM-treated groups (Table 4).
|
). LDL-r protein levels in both Dron-treated groups did not differ from the LDL-r protein levels in the livers of control animals. However, in the Am100 group LDL-r protein expression was decreased (P < 0.004; Fig. 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1 and has no effect on T3 binding to TRß1. In contrast, the metabolite DBDron was a very potent inhibitor of T3 binding to TR1, but a weak inhibitor of T3 binding to TRß1. Dron and DBDron are, like AM and DEA, strong lipophilic compounds, not easily dissolved in an aqueous environment. To keep the compounds in solution, we added 0.025% Triton X-100 to the assay buffer, which has no effect on affinity (12). The solubility of Dron and DBDron was tested at OD400. No opacity (precipitation) was observed at concentrations up to 100 µM, but OD400 rose in an exponential manner at higher concentrations. The IC50 value of DBDron with respect to TRß1 could therefore not be measured directly, but was estimated by extrapolation from the dose-response curve. It appears that the inhibitory effect of DBDron is about 4.7 times greater for T3 binding to TR1 than to TRß1. From the Scatchard plots and Langmuir analysis it is evident that the inhibitory effect of DBDron on T3 binding to TR1 is competitive in nature. We were unable to obtain reliable data on the type of inhibition by DBDron of TRß1 because we could not add sufficient amounts of DBDron to reach concentrations around the IC50 value of 280 µM, as the drug came out of solution at concentrations of approximately 100 µM.
The effect of Dron is similar to that of AM in so far that not the parent drug, but its metabolites DBDron and DEA, respectively, are the potent inhibitors of T3 binding to the TR. Although DBDron is less potent than DEA in this respect by a factor of 2 for TR1 and 4 for TRß1 the two metabolites differ markedly from each other in that DBDron inhibits T3 binding to TR1 but much less to TRß1, whereas DEA clearly inhibits T3 binding to both TR1 and TRß1 within the same order of magnitude.
The quantitative differences between DEA and DBDron with respect to inhibiting T3 binding to TR1 and TRß1 are most likely the result of differences in structures between the two compounds and/or between the two receptors. The ligand binding domain of the cTR1 and hTRß1 are 89% homologous. The differences in the amino acid sequences between cTR1 and hTRß1 are mainly located in strand 3/helix 3, in strand 7/helix 7, and in helix 10. Studying the three-dimensional structure of the hTRß1 (PDB Id: 1BSX, studied using Cn3D v. 3.0 via the NCBI web site), it becomes apparent that some of the differences between TR1 and TRß1 in helix 10 are on the same surface side of the receptor as amino acids R429 and E457, which we demonstrated in earlier studies (9) to be involved in DEA interaction to TRß1. These differences in amino acid sequences can lead to subtle changes in the three-dimensional structure for TR1 compared with TRß1. The chemical structures of DEA and DBDron have great similarity, but there are some important differences. DEA has two bulky iodine atoms, which DBDron has not. The amino side-chain of DBDron is longer and has a butyl group instead of an ethyl group. It is possible that the extra methanesulfonamide group in the DBDron molecule, which carries a positive charge, is of importance in explaining the decreased affinity to TRß1 compared with TR1.
The competitive nature suggests competition between T3 and DEA or DBDron at the same binding site on the TR1. However, it is also possible that T3 and DEA or DBDron do not bind in the same binding pocket, but that the binding of DEA or DBDron to the receptor will change the structure of the TR1 binding pocket in such a way that T3 can no longer bind to TR1. This conformational change could in vivo result in a reduction of the available binding sites for T3 binding on the TR1 in tissues when DEA and DBDron are bound. The binding of T3 and DEA or DBDron to the TRs is a reversible process, and its equilibrium is dependent on the concentrations of the compounds present. When the concentrations of DEA or DBDron in tissue rises because of the accumulation of the drug metabolites, the binding of T3 to the TRs will decrease, resulting in a decrease in T3-dependent gene expression.
In vivo studies
The in vitro data suggest that DBDron could act as a selective antagonist to TR1. Such an effect in vivo would require tissue concentrations of DBDron remaining below the IC50 value of 280 µM. In dogs treated orally with Dron (20 mg/kg·d) for 4 wk, the myocardial content of Dron is 23 µmol/kg, and that of DBDron is 6 µmol/kg (13). In the same study dogs treated with AM (40 mg/kg·d) for 4 wk had myocardial concentrations of 28 µmol/kg AM and 21 µmol/kg DEA. Dron and DBDron concentrations in human tissues are not known, but AM and DEA concentrations are 62 and 274 µmol/kg, respectively, in human hearts obtained from autopsies (14). The human tissue concentrations are higher than in the dog studies, probably related to the accumulation of AM and DEA in tissues upon long-term treatment of patients with AM. The DEA concentrations in the human heart are much higher than the IC50 values of DEA for TR1 and TRß1 and allow for an antagonistic effect in vivo on T3-dependent gene expression mediated via both receptor isoforms. The few available data on DBDron content in the heart are compatible with the idea that DBDron concentrations will not be sufficiently high to exert an antagonistic effect on TRß1, but will allow antagonism to TR1. If so, this could be of clinical relevance. The heart has an abundance of TR1 relative to TRß1, whereas tissues such as the liver express TRß1 more abundantly than TR1 (15). AM and Dron have similar electrophysiological effects on the heart (13, 16, 17, 18), and their antiarrhythmic effect might well be mediated at least partly via TR1 by inducing a local hypothyroid-like condition (19). One of the side-effects of amiodarone is an increase in plasma cholesterol caused by a down-regulation of the T3-dependent LDL-r gene in the liver (2, 3).
Because of the higher affinity of DBDron to TR1, we hypothesized that the effect of Dron on heart rate and Qtc interval would be similar to that of AM, but that Dron, in contrast to AM, will not cause hypercholesterolemia and changes in liver LDL-r expression, as T3-induced changes in cholesterol metabolism are mainly mediated via TRß1 (20).
Our in vivo experiments support this hypothesis. First, Dron and AM had differential effects on thyroid hormone metabolism. AM, but not Dron, caused a decrease in the activity of liver D1, the enzyme responsible for the generation of T3 from T4 and the degradation of rT3 into 3,3'-diiodothyronine. As the liver is the main site for production of T3 and the degradation of rT3, the decrease in plasma T3 and the increase in plasma rT3 upon AM treatment are explained by the fall in liver D1 activity in agreement with previous studies (Ref. 21 and references therein). The gene encoding D1 is under thyroid hormone control, an effect mainly mediated via TRß1 (22). The absence of an effect of Dron on liver D1 activity could thus be taken as evidence in favor of Dron not interfering with T3 binding to TRß1, but the available evidence suggests another mechanism. AM treatment is not associated with a fall in liver D1 mRNA (Refs. 2 and 21 and references therein), but the decrease in liver D1 activity is due to less availability of the substrate T4 caused by inhibition of cellular T4 uptake and direct inhibition of D1 by amiodarone (21), which frequently results in higher T4 and FT4 levels.
Dron treatment tends to decrease plasma TSH, whereas AM, in contrast, gives rise to higher TSH levels. The TSH increase caused by AM is explained by the iodine excess generated by the drug, as has been reported previously (Ref. 1 and references therein). Dron treatment is associated with a decrease in total and free T4 and T3 concentrations. The decreases in T4 and T3 cannot be explained from changes in plasma thyroid hormone-binding proteins, because the T3 uptake measurements in plasma remained unchanged, nor from changes related to nonthyroidal illness, because plasma rT3 remained unaltered. Although an effect of diminished food intake cannot be excluded, the lower T4 and T3 production by the thyroid gland might be the result of diminished TSH secretion.
TSH secretion is under negative thyroid hormone control, an effect mediated mainly by TRß1, but the pituitary thyrotrophs also contain TR1 (23, 24, 25). In TR1-/- mice, lower plasma TSH levels are observed as a result of a decreased expression of the TSH -subunit (26). Therefore, our in vivo data showing decreased T4 and T3 levels and slightly lower TSH in Dron-treated rats might be interpreted as resulting from a TR1-selective inhibition of T3 binding by Dron.
Secondly, we observed a lengthening of the QTc interval in rats treated with either AM or Dron, a typical effect of class III antiarrhythmic drug. It has been suggested in the case of AM that part of this increase can be explained by its inhibition of the binding of T3 to TR in the heart (19). Recently, it was shown that TR1 is the isoform involved in setting the heart rate (15, 26). Deleting TR1 not only lowers the heart rate, but also increases the QTc interval. This fits with our data for Dron and AM. When we combine the results of our in vitro and in vivo studies, the lengthening of the QTc interval would be the result of a selective inhibition of T3 binding to TR1 in the heart.
Thirdly, we did not observe a change in plasma cholesterol or liver LDL-r expression in rats treated with Dron. AM-induced hypercholesterolemia cannot be explained by the rise in TSH, because even higher TSH levels in mildly hypothyroid animals do not result in an increase in plasma cholesterol (2). The increase in plasma cholesterol by AM, which acts on both TR1 and TRß1, can be explained by a decreased expression of LDL-r in the liver at both mRNA and protein levels (3). It has recently become clear that most of the regulation of cholesterol metabolism and LDL-r expression in liver is TRß1 dependent (20). Thus, the lack of effect of Dron on plasma cholesterol and LDL-r expression can be explained by our in vitro data showing that Dron is a TR1-selective inhibitor.
In conclusion, the in vitro and in vivo data presented in this paper indicate that Dron, via its metabolite DBDron, is a TR1-selective inhibitor of T3 binding to its receptor. This isoform selectivity can explain the effects of Dron on the heart (a mainly TR1 organ) and the lack of effect on the liver (a mainly TRß1 organ) and may also point the way to designing TR isoform-specific antagonists.
|
Footnotes |
|---|
1, thyroid hormone receptor 1. Received June 10, 2002.
Accepted for publication October 16, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
1-receptor protein. Mol Cell Endocrinol 112:15–19[CrossRef][Medline]
1-and ß1 thyroid hormone receptor by amiodarone analogs. Endocrinology 137:2807–2814[Abstract]
or ß. Endocrinology 142:544–550 and ß genes. J Endocrinol 172:177–185[Abstract]
1. EMBO J 15:455–461[CrossRef]This article has been cited by other articles:
 |
|
 |
|
  G. J. Grover, C. Dunn, N.-H. Nguyen, J. Boulet, G. Dong, J. Domogauer, P. Barbounis, and T. S. Scanlan Pharmacological Profile of the Thyroid Hormone Receptor Antagonist NH3 in Rats J. Pharmacol. Exp. Ther., July 1, 2007; 322(1): 385 - 390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Stoykov, H C van Beeren, A F M Moorman, V M Christoffels, W M Wiersinga, and O Bakker Effect of amiodarone and dronedarone administration in rats on thyroid hormone-dependent gene expression in different cardiac components Eur. J. Endocrinol., June 1, 2007; 156(6): 695 - 702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M Dale and C M. White Dronedarone: An Amiodarone Analog for the Treatment of Atrial Fibrillation and Atrial Flutter Ann. Pharmacother., April 1, 2007; 41(4): 599 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Tafreshi and J. Rowles A Review of the Investigational Antiarrhythmic Agent Dronedarone Journal of Cardiovascular Pharmacology and Therapeutics, March 1, 2007; 12(1): 15 - 26. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Flamant, J. D. Baxter, D. Forrest, S. Refetoff, H. Samuels, T. S. Scanlan, B. Vennstrom, and J. Samarut International Union of Pharmacology. LIX. The Pharmacology and Classification of the Nuclear Receptor Superfamily: Thyroid Hormone Receptors Pharmacol. Rev., December 1, 2006; 58(4): 705 - 711. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Tedelind, F. Larsson, C. Johanson, H. C. van Beeren, W. M. Wiersinga, E. Nystrom, and M. Nilsson Amiodarone Inhibits Thyroidal Iodide Transport in Vitro by a Cyclic Adenosine 5'-Monophosphate- and Iodine-Independent Mechanism Endocrinology, June 1, 2006; 147(6): 2936 - 2943. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Stoykov, B Zandieh-Doulabi, A F M Moorman, V Christoffels, W M Wiersinga, and O Bakker Expression pattern and ontogenesis of thyroid hormone receptor isoforms in the mouse heart. J. Endocrinol., May 1, 2006; 189(2): 231 - 245. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
), Dron (
), and DBDron (
). Values are given as the mean ± SD (n = 5) and are expressed as the percentage of specifically bound [125I]T3 in the absence of the compounds.
BW, plasma thyroid hormones, and plasma lipids