Effects of Triiodothyronine and Amiodarone on the Promoter of the Human LDL Receptor Gene

Bakker, O.; Hudig, Francisca; Meijssen, S.; Wiersinga, Wilmar M.

doi:10.1006/bbrc.1998.9174

Cited by 94 publications

(64 citation statements)

References 25 publications

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“…Our data clearly demonstrate that DEA, but not amiodarone, exerts a direct effect on genes that are either positively or negatively regulated by thyroid hormone: this effect is direct and specific and occurs only in the presence of TR and a TRE. Our results expand those of Bakker et al (19), who found that, in transient transfection assays, Figure 4 Effect of amiodarone (AMIO) and DEA on TR binding to ME-TRE. EMSA was performed using a synthetic oligonucleotide containing the ME-TRE sequence as a 32 P-labelled probe.…”

Section: Discussionsupporting

confidence: 89%

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

Bogazzi

Bartalena

Brogioni

et al. 2001

European Journal of Endocrinology

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Objective: To evaluate the molecular mechanisms of the inhibitory effects of amiodarone and its active metabolite, desethylamiodarone (DEA) on thyroid hormone action. Materials and methods: The reporter construct ME-TRE-TK-CAT or TSHb-TRE-TK-CAT, containing the nucleotide sequence of the thyroid hormone response element (TRE) of either malic enzyme (ME) or TSHb genes, thymidine kinase (TK) and chloramphenicol acetyltransferase (CAT) was transiently transfected with RSV-TRb into NIH3T3 cells. Gel mobility shift assay (EMSA) was performed using labelled synthetic oligonucleotides containing the ME-TRE and in vitro translated thyroid hormone receptor (TR)b. Results: Addition of 1 mmol/l T 4 or T 3 to the culture medium increased the basal level of ME-TRE-TK-CAT by 4.5-and 12.5-fold respectively. Amiodarone or DEA (1 mmol/l) increased CAT activity by 1.4-and 3.4-fold respectively. Combination of DEA with T 4 or T 3 increased CAT activity by 9.4-and 18.9-fold respectively. These data suggested that DEA, but not amiodarone, had a synergistic effect with thyroid hormone on ME-TRE, rather than the postulated inhibitory action; we supposed that this was due to overexpression of the transfected TR into the cells. When the amount of RSV-TRb was reduced until it was present in a limited amount, allowing competition between thyroid hormone and the drug, addition of 1 mmol/l DEA decreased the T 3 -dependent expression of the reporter gene by 50%. The inhibitory effect of DEA was partially due to a reduced binding of TR to ME-TRE, as assessed by EMSA. DEA activated the TR-dependent down-regulation by the negative TSH-TRE, although at low level (35% of the down-regulation produced by T 3 ), whereas amiodarone was ineffective. Addition of 1 mmol/l DEA to T 3 -containing medium reduced the T 3 ±TR-mediated down-regulation of TSH-TRE to 55%. Conclusions: Our results demonstrate that DEA, but not amiodarone, exerts a direct, although weak, effect on genes that are regulated by thyroid hormone. High concentrations of DEA antagonize the action of T 3 at the molecular level, interacting with TR and reducing its binding to TREs. This effect may contribute to the hypothyroid-like effect observed in peripheral tissues of patients receiving amiodarone treatment.

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Section: Discussionsupporting

confidence: 89%

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

Bogazzi

Bartalena

Brogioni

et al. 2001

European Journal of Endocrinology

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“…Thyroid hormone decreases serum cholesterol concentration by the removal of cholesterol from the liver via the increased LDL receptors [17,18] and serum TG concentration by enhancing lipoprotein lipase and hepatic lipase activities [19][20][21]. Thus, a higher population of hypothyroid subjects had a higher incidence of dyslipidemia [22].…”

Section: Discussionmentioning

confidence: 99%

Multi-center study on the prevalence of hypothyroidism in patients with hypercholesterolemia

et al. 2011

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abstract. Hypercholesterolemia is one of the most representative disorders of the common diseases. To evaluate the prevalence of hypothyroidism in the population of adult hypercholesterolemia, we prospectively examined the thyroid function in patients with untreated or treated hypercholesterolemia as a multi-center survey. Subjects were the patients who were treated with some antilipemic agents or the untreated patients whose total cholesterol (TC) was over 220 mg/dL and/or LDL-cholesterol (LDL-C) over 140 mg/dL. Among 737 cases recruited, 725 cases (300 males and 425 females) participated in the survey including the thyroid function test. The patient's backgrounds include hypertension (51%), diabetes mellitus (49%), fatty liver (17%), smoking (15%), and habitual drinking (10%). The 72% of the patients were treated with some antilipemic agents and the mean values of TC, LDL-C, triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-C/HDL-C ratio were 204.5 mg/dL, 119.6 mg/dL, 144.4 mg/dL, 60.7 mg/dL and 2.25, respectively. The primary hypothyroidism was seen in 27 cases (3.7%) (11 males, 16 females) with subclinical hypothyroidism in 17 cases (2.4%) and overt hypothyroidism in 10 cases (1.4%). The central hypothyroidism was seen in 4 cases (0.6%). The prevalence of hypothyroidism was 4.3% in patients with hypercholesterolemia. Taking account of the large number of patients with dyslipidemia and importance of avoiding unnecessary administration and associated adverse effects, evaluation of the thyroid function could be warranted in patients with dyslipidemia although cost-benefit issues waits further investigation.Key words: Hypercholesterolemia, Dyslipidemia, Subclinical hypothyroidism strongly related to atherosclerotic cardiovascular disease. Recently, new therapeutic reagents such as fibrates and statins have been created and primary dyslipidemia is effectively treated with these reagents [1]. However, they are not low priced and may induce rare but serious side effects such as rhabdomyolysis [1]. Hypothyroidism induces secondary hypercholesterolemia that increases the incidence of atherosclerotic cardiovascular events [2], and replacement of low-

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“…Amiodarone, or most probably DEA, may interfere with nuclear receptor/coactivator interaction. 31,32 It reduces basal LDL receptor promoter activity. It also disrupts the interaction between the glucocorticoid receptor interacting protein-1 and the thyroid hormone receptor ␤1.…”

Section: Le Bouter Et Al Pharmacogenomics Of Amiodarone 3033mentioning

confidence: 99%

Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart

et al. 2004

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Background-The basis for the unique effectiveness of long-term amiodarone treatment on cardiac arrhythmias is incompletely understood. The present study investigated the pharmacogenomic profile of amiodarone on genes encoding ion-channel subunits. Methods and Results-Adult male mice were treated for 6 weeks with vehicle or oral amiodarone at 30, 90, or 180 mg · kg Ϫ1 · d Ϫ1. Plasma and myocardial levels of amiodarone and N-desethylamiodarone increased dose-dependently, reaching therapeutic ranges observed in human. Plasma triiodothyronine levels decreased, whereas reverse triiodothyronine levels increased in amiodarone-treated animals. In ECG recordings, amiodarone dose-dependently prolonged the RR, PR, QRS, and corrected QT intervals. Specific microarrays containing probes for the complete ion-channel repertoire (IonChips) and real-time reverse transcription-polymerase chain reaction experiments demonstrated that amiodarone induced a dose-dependent remodeling in multiple ion-channel subunits. Genes encoding Na ϩ (SCN4A, SCN5A, SCN1B), connexin (GJA1), Ca 2ϩ (CaCNA1C), and K ϩ channels (KCNA5, KCNB1, KCND2) were downregulated. In patch-clamp experiments, lower expression of K ϩ and Na ϩ channel genes was associated with decreased I to,f , I K,slow , and I Na currents. Inversely, other K ϩ channel ␣-and ␤-subunits, such as KCNA4, KCNK1, KCNAB1, and KCNE3, were upregulated. Conclusions-Long-term amiodarone treatment induces a dose-dependent remodeling of ion-channel expression that is correlated with the cardiac electrophysiologic effects of the drug. This profile cannot be attributed solely to the amiodarone-induced cardiac hypothyroidism syndrome. Thus, in addition to the direct effect of the drug on membrane proteins, part of the therapeutic action of long-term amiodarone treatment is likely related to its effect on ion-channel transcripts. Key Words: antiarrhythmic agents Ⅲ ion channels Ⅲ molecular biology Ⅲ electrophysiology A miodarone, a widely used antiarrhythmic drug, has remarkable efficacy for the treatment of ventricular tachyarrhythmias and atrial fibrillation. However, the basis for its effectiveness is still poorly understood. The pharmacologic profile of this drug is complex, and much remains to be clarified about both short-and long-term actions. Amiodarone has been referred to as a class III antiarrhythmic agent, 1 but it also possesses electrophysiologic characteristics of class I and IV agents and minor class II effects. 2 The drug is also known to modify thyroid function extensively because of its iodinated nature. 3 The question arose as to whether the long-term effects of amiodarone might stem from its molecular interaction with thyroid hormone receptors or other mechanisms. In particular, it has been hypothesized that the effects of amiodarone could depend on modulation of transcript expression in addition to its direct effect on cell membrane channels. 4 Genomic techniques now bring gene expression studies to a genome scale, allowing investigators to examine simultaneous changes in th...

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Effects of Triiodothyronine and Amiodarone on the Promoter of the Human LDL Receptor Gene

Cited by 94 publications

References 25 publications

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

Desethylamiodarone antagonizes the effect of thyroid hormone at the molecular level

Multi-center study on the prevalence of hypothyroidism in patients with hypercholesterolemia

Long-Term Amiodarone Administration Remodels Expression of Ion Channel Transcripts in the Mouse Heart

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