Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone α1-receptor protein

doi:10.1016/0303-7207(95)03578-U

Molecular and Cellular Endocrinology

Volume 112, Issue 1, July 1995, Pages 15-19

https://doi.org/10.1016/0303-7207(95)03578-U Get rights and content

Abstract

Desethylamiodarone (DEA), the major metabolite of the potent antiarrythmic drug amiodarone, is a non-competitive inhibitor of the binding of thyroid hormone (T₃) to the β1-thyroid hormone receptor (T₃R). In the present study, we investigated whether DEA acts in a similar way with respect to the α1-T₃R. The chicken α1-T₃R, expressed in an E. coli system, was incubated in the presence or absence of DEA with [¹²⁵I]T₃ in buffer containing 0.05% Triton X-100, 0.05% BSA and 1% ethanol (v/v) in order to solubilise DEA. DEA, but not amiodarone, inhibited T₃ binding in a dose-dependent manner; the IC₅₀ value was 3.5 × 10⁻⁵ M. Scatchard analyses in the presence of DEA demonstrated a dose-dependent decrease in K_a values, but no change in MBC. Lineweaver-Burk plots clearly indicated competitive inhibition by DEA. Pre-incubation of the α1-receptor with DEA decreased maximal [¹²⁵I]T₃ binding, which was independent of the duration of pre-incubation. In conclusion, in contrast to the β1-T₃R, where DEA acts as a non-competitive inhibitor, we now report as a new finding the competitive action of DEA to the α1-T₃R.

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Cited by (57)

Amiodarone and thyroid physiology, pathophysiology, diagnosis and management
2019, Trends in Cardiovascular Medicine
Citation Excerpt :
Some of the cardiovascular effects of amiodarone/DEA have been attributed to their ability to decrease thyroid hormone signaling in the myocardium, resulting in less thyroid hormone action [60]. The chemical structures of amiodarone and DEA are very similar to T3, and both have been shown to inhibit thyroid hormone transport across the plasma membrane [61], and/or direct binding to the thyroid hormone receptors, TRα and TRβ [62,63] and possibly even TR-dependent gene transcription [64]. The healthy human (but not rodent) myocardium expresses D2 and thus is capable of generating T3 inside the muscle fiber.
Although amiodarone is considered the most effective antiarrhythmic agent, its use is limited by a wide variety of potential toxicities. The purpose of this review is to provide a comprehensive “bench to bedside” overview of the ways amiodarone influences thyroid function. We performed a systematic search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1950 and 2017. Amiodarone was searched using the terms adverse effects, hypothyroidism, myxedema, hyperthyroidism, thyroid storm, atrial fibrillation, ventricular arrhythmia, and electrical storm. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. We included 163 germane references in this review. Because amiodarone is one of the most frequently prescribed antiarrhythmic drugs in the United States, the mechanistic, diagnostic and therapeutic information provided is relevant for practicing clinicians in a wide range of medical specialties.
Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules
2018, Vitamins and Hormones
Citation Excerpt :
Structurally similar to T3 and T4, amiodarone is rich in iodine and has been linked to the development of hyperthyroidism. Conversely, the amiodarone metabolite desethylamiodarone has been shown to be a noncompetitive antagonist of TRβ1 (Bakker, van Beeren, & Wiersinga, 1994) and a TRα competitive antagonist (van Beeren, Bakker, & Wiersinga, 1995) and leads to the development of hypothyroidism. The dual effects of amiodarone have been demonstrated in the Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) (Batcher et al., 2007).
Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism.
Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people.
This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution.
Neuroendocrine regulation of development, growth and metabolism - thyroid
2012, Handbook of Neuroendocrinology
This chapter focuses on various aspects of thyroidology and the role of thyroid hormone in normal development and for adult health. The mature human and rodent thyroid gland consists of two elongated oval lobes, one on each side of the trachea, joined near their posterior poles by a thin isthmus crossing the trachea ventrally. There are several physiological implications of the anatomy of the thyroid gland and the chemistry of thyroid hormone. First, the observation that iodinated thyroglobulin is stored in large quantities in the adult thyroid gland indicates that there is a great deal of resilience in the system. The thyroid gland is controlled principally and proximally by an interaction between iodine availability — a requirement for thyroid hormone synthesis — and thyrotropin (TSH) from the pituitary gland. This is true for humans and rodents, as well as for other vertebrates. The use of transgenic mouse models has led to important progress in clarifying the relative roles of the hypothalamus and pituitary in controlling thyroid function.
Amiodarone and thyroid
2009, Best Practice and Research: Clinical Endocrinology and Metabolism
Citation Excerpt :
Indeed, AM treatment is associated with decreased SERCA2a and αMHC and increased βMHC gene expression in the heart, closely resembling the changes in systemic hypothyroidism.6 Mechanisms by which DEA causes changes in the expression of these T3-dependent genes include inhibition of T3 binding to thyroid hormone receptors (TRs), inhibition of co-activator binding to TR and inhibition of TR binding to the thyroid hormone responsive element (TRE).7–10 The findings support the hypothesis of a local hypothyroid-like condition in the heart induced by AM.11
Assessment of TSH and TPO-Ab before starting amiodarone (AM) treatment is recommended. The usefulness of periodic TSH measurement every 6 months during AM treatment is limited by the often sudden explosive onset of AIT, and the spontaneous return of a suppressed TSH to normal values in half of the cases. AM-induced hypothyroidism develops rather early after starting treatment, preferentially in iodine-sufficient areas and in females with TPO-Ab; it is due to failure to escape from the Wolff–Chaikoff effect, resulting in preserved radioiodine uptake. AM-induced thyrotoxicosis (AIT) occurs at any time during treatment, preferentially in iodine-deficient regions and in males. AIT can be classified in type 1 (iodide-induced thyrotoxicosis, best treated by potassium perchlorate in combination with thionamides and discontinuation of AM) and type 2 (destructive thyrotoxicosis, best treated by prednisone; discontinuation of AM may not be necessary). AIT is associated with a higher rate of major adverse cardiovascular events (especially of ventricular arrhythmias). Uncertainty continues to exist with respect to the feasibility of continuation of AM despite AIT, the appropriate methods to distinguish between AIT type 1 and 2 as well as the advantages of AIT classification into subtypes in view of possible mixed cases, and the best policy when AM needs to be restarted.
Thyroid hormone and myocardial ischaemia
2008, Journal of Steroid Biochemistry and Molecular Biology
Thyroid hormone has various effects on the cardiovascular system and its effects on cardiac contractility, heart rhythm and vascular function has long been recognized. However, new evidence is emerged on the importance of thyroid hormone in the response of the myocardium to ischaemic stress and cardiac remodelling following myocardial infarction. Based on this new information, this review highlights the role of thyroid hormone in myocardial ischaemia and cardiac remodelling, the possible underlying mechanisms and the potential therapeutic implications. Thyroid hormone or analogs may prove new therapeutic agents for treating ischaemic heart disease.
Long-term amiodarone treatment causes cardioselective hypothyroid-like alteration in gene expression profile
2008, European Journal of Pharmacology
The long-term cardiac effects of amiodarone resemble many aspects of hypothyroidism. The anti-arrhythmic potential of amiodarone may therefore be the result of a drug-induced, local hypothyroid-like condition. To investigate this controversial issue, we compared gene expression profiles in the hearts of rats treated with amiodarone with those of rats with hypothyroidism. Wistar male rats were assigned to 3 groups (n = 6–8): Control, systemic hypothyroidism (Hypothyroidism) and amiodarone treatment (Amiodarone, 150 mg/kg/day, p.o., 4 weeks). Electrocardiogram (ECG) recordings, gene profiling by DNA microarray and Northern blotting were carried out. Amiodarone, like Hypothyroidism, caused significant prolongation of RR and QT intervals in ECGs. Microarray analysis of 8435 genes in the left ventricular myocardium revealed a significant similarity in expression profiles between Hypothyroidism and Amiodarone (R = 0.63, p < 0.00001). The gene expression profiles of Hypothyroidism and Amiodarone showed closer correlation when top 100 up-regulated and 100 down-regulated genes in Hypothyroidism (total 200 genes) were analyzed (R = 0.78, p < 0.00001). Northern blots of left ventricular myocardium showed a parallel decrease in mRNAs for myosin heavy chain (MHC)-alpha and a parallel increase for myosin heavy chain (MHC)-beta in Hypothyroidism and Amiodarone. In the liver and pituitary, in contrast, Northern blots showed quite different changes in the transcripts of the representative T3-responsive genes in the Hypothyroidism and Amiodarone. In conclusion, long-term treatment with amiodarone causes cardioselective hypothyroid-like alterations in gene expression profiles. The potent anti-arrhythmic activity of amiodarone may be attributable, in part at least, to this unique transcriptional remodeling.

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Research paperDesethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone α1-receptor protein

Abstract

FEBS Lett.

Biochem. Biophys. Res. Commun.

Endocrinology

Horm. Metab. Res.

Eur. J. Endocrinol.

Research paper
Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone α1-receptor protein