Inhibition of the Type 2 Iodothyronine Deiodinase Underlies the Elevated Plasma TSH Associated with Amiodarone Treatment

Rosene, Matthew L.; Wittmann, Gábor; Arrojo e Drigo, Rafael; Singru, Praful S.; Lechan, Ronald M.; Bianco, Antonio C.

doi:10.1210/en.2010-0553

Cited by 72Thyroid Disorders and TreatmentsAdrenal Hormones and DisordersPharmacogenetics and Drug Metabolism

Inhibition of the Type 2 Iodothyronine Deiodinase Underlies the Elevated Plasma TSH Associated with Amiodarone Treatment

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Rosene, Matthew L., Wittmann, Gábor, Arrojo e Drigo, Rafael, Singru, Praful S., Lechan, Ronald M., Bianco, Antonio C.·2010·Endocrinology

DOI 10.1210/en.2010-0553PMC PMC2999495

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Abstract

The widely prescribed cardiac antiarrhythmic drug amiodarone (AMIO) and its main metabolite, desethylamiodarone (DEA), have multiple side effects on thyroid economy, including an elevation in serum TSH levels. To study the AMIO effect on TSH, mice with targeted disruption of the type 2 deiodinase gene (D2KO) were treated with 80 mg/kg AMIO for 4 wk. Only wild-type (WT) mice controls developed the expected approximate twofold rise in plasma TSH, illustrating a critical role for D2 in this mechanism. A disruption in the D2 pathway caused by AMIO could interfere with the transduction of the T4 signal, generating less T3 and softening the TSH feedback mechanism. When added directly to sonicates of HEK-293 cells transiently expressing D2, both AMIO and DEA behaved as noncompetitive inhibitors of D2 [IC(50) of >100 μm and ∼5 μm, respectively]. Accordingly, D2 activity was significantly decreased in the median eminence and anterior pituitary sonicates of AMIO-treated mice. However, the underlying effect on TSH is likely to be at the pituitary gland given that in AMIO-treated mice the paraventricular TRH mRNA levels (which are negatively regulated by D2-generated T3) were decreased. In contrast, AMIO and DEA both exhibited dose-dependent inhibition of D2 activity and elevation of TSH secretion in intact TαT1 cells, a pituitary thyrotroph cell line used to model the TSH feedback mechanism. In conclusion, AMIO and DEA are noncompetitive inhibitors of D2, with DEA being much more potent, and this inhibition at the level of the pituitary gland contributes to the rise in TSH seen in patients taking AMIO.

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A need for increased LT4 dose was reported with initiation of amiodarone therapy in two patients, and amiodarone inhibits D2 in rodents.
“With respect to agents that alter D2 activity, a need for an increased dose of LT4 was reported with initiation of amiodarone therapy in two patients (192), and this drug has been shown to inhibit D2 in rodents (193).”
From Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement (2014) · cites this paper as [193]

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Authors: Rosene, M. L., Wittmann, G., Arrojo e Drigo, R., Singru, P. S., Lechan, R. M., & Bianco, A. C.
Affiliations: University of Miami (US)
Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism (G.W., P.S.S., R.M.L.), Tufts Medical Center and Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts 02111
Division of Endocrinology, Diabetes, and Metabolism (M.L.R., R.A.e.D., A.C.B.), University of Miami Miller School of Medicine, Miami, Florida 33136
Tufts University (US)
Corresponding author: Bianco, Antonio C.
ORCID: Singru, Praful S.
Lechan, Ronald M.
Bianco, Antonio C.
Venue: Endocrinology
Publisher: The Endocrine Society
Published: 2010-10-06
Volume: 151
Issue: 12
Pages: 5961-5970
ISSN: 0013-7227 (ISSN-L)
1945-7170
DOI: 10.1210/en.2010-0553
PMC: PMC2999495
OpenAlex: W1996253654
Cited by: 72
References: 39
Citations by year: 2025: 2 · 2024: 2 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 6 · 2017: 9 · 2016: 6 · 2015: 7 · 2014: 5 · 2013: 5 · 2012: 7
FWCI: 4.34
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Endocrinology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Diabetes and Digestive and Kidney Diseases (DK 37021, R01DK058538, R01DK037021, DK 58538, R56DK037021)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
Keywords: amiodarone, desethylamiodarone, type 2 deiodinase, TSH elevation, thyroid-stimulating hormone, non-competitive inhibition, T3, thyrotropin-releasing hormone, pituitary gland, adverse drug reactions, antiarrhythmic drugs
MeSH terms: Iodothyronine Deiodinase Type II, Amiodarone, Animals, Anti-Arrhythmia Agents, Cell Line, Iodide Peroxidase, Mice, Inbred C57BL, Thyrotropin, Mice, Knockout, Mice

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Inhibition of the Type 2 Iodothyronine Deiodinase Underlies the Elevated Plasma TSH Associated with Amiodarone Treatment

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