The DOI matches its Crossref record; 16 of the 16 references it cites were found in a registry or an index.
Studies on the in vitro cytotoxic effect of amiodarone.
Abstract
Amiodarone, a potent antiarrhythmic drug, contains 37.2% iodine by weight and may induce either hypo- or hyperthyroidism. The high iodine content of amiodarone may be responsible for both complications, but a cytotoxic effect of the drug on the thyroid resulting in thyroiditis has been reported. In the present study the cytotoxic effect of amiodarone was evaluated in three culture systems with different biological properties: 1) a strain of rat thyroid cells (FRTL-5 cells) that maintains most differentiated functions of normal thyroid cells, including an active iodide pump, but an inability to organify iodide; 2) a line of Chinese hamster ovary (CHO) fibroblasts; and 3) freshly prepared primary cultures of human thyroid follicles (hTF) that trap and organify iodide. Cells were radiolabeled with 51Cr and incubated for 24 h with medium alone, medium plus amiodarone (3.75-200 microM), medium plus an iodinated radiographic contrast agent (sodium diatrizoate; 7.5-200 microM), or medium plus potassium iodide (7.5-300 microM). At concentrations ranging from 75-200 microM, amiodarone induced a significant and dose-dependent release of 51Cr in FRTL-5 cells. In contrast, diatrizoate or KI had no cytotoxic effect on FRTL-5 cells. In the same molar concentrations, amiodarone was also cytotoxic in CHO cells. In hTF, the release of 51Cr produced by amiodarone occurred at a lower concentration (37.5 vs. 75 microM) and was significantly greater than that in FRTL-5 cells. The cytotoxic effect of amiodarone in hTF was partially, but significantly, reduced by methimazole, an inhibitor of iodide organification. In the FRTL-5 cell culture system, amiodarone also produced a dramatic inhibition of TSH-stimulated cell growth. This growth-inhibiting effect of amiodarone was evident at low concentrations (3.75-7.5 mumol/liter) of the drug, which did not produce significant cytotoxicity. In conclusion, 1) amiodarone had a cytotoxic effect in CHO fibroblasts, a nonthyroid cell line; 2) this cytotoxic effect occurred in thyroid cells independent of their ability to organify iodide; 3) however, the toxic effect of amiodarone was greater and occurred at a lower molar concentration in freshly prepared human thyroid follicles that trap and organify iodide; and 4) in the latter culture system, methimazole, an inhibitor of iodide organification, partially, but significantly, reduced the cytotoxic effect of amiodarone. These data suggest that thyroid cytotoxicity produced by amiodarone is mainly due to a direct effect of the drug on thyroid cells, but excess iodide released from the drug may contribute to its toxic action.
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In the citing paper
“Two distinct mechanisms have been proposed in the development of AIT, including an iodine-induced form of hyperthyroidism (type 1 AIT) due to the high iodine content of amiodarone (37% by molecular weight) and a destructive thyroiditis (type 2 AIT) due to direct toxicity of amiodarone on follicular cells.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [580]
In the citing paper
“Type 1 AIT tends to occur in patients with underlying thyroid autonomy in a nodular goiter, or GD, whereas type 2 AIT occurs as a result of direct damage or induction of apoptosis in thyrocytes by amiodarone (579-582).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [580]
Citations
Cites
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Iodide Transport in a Continuous Line of Cultured Cells from Rat Thyroid
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Serum interleukin-6 in amiodarone-induced thyrotoxicosis
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Self-citationAMIODARONE IODINE‐INDUCED HYPOTHYROIDISM: RISK FACTORS AND FOLLOW‐UP IN 28 CASES
Martino, E., Aghini-Lombardi, F., Mariotti, S., Bartalena, L., Lenziardi, M., Ceccarelli, C., Bambini, G., Safran, M., Braverman, L. E., & Pinchera, A. (1987) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1987.tb00781.x · Cited by 119
Self-citationThyroidectomy for Amiodarone-Induced Thyrotoxicosis
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In vitro study of acute toxic effects of high iodide doses in human thyroid follicles
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Self-citationRoti, E., Minelli, R., Gardini, E., Bianconi, L., Gavaruzzi, G., Ugolotti, G., Neri, T. M., & Braverman, L. E. (1992) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.75.5.1331165 · Cited by 51
Self-citationIodine-Induced Hypothyroidism in Euthyroid Subjects with a Previous Episode of Subacute Thyroiditis*
Roti, E., Minelli, R., Gardini, E., Bianconi, L., & Braverman, L. E. (1990) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-70-6-1581 · Cited by 46
Self-citationThyroid cell growth, differentiation and function in the FRTL-5 cell line: a survey
Bidey, S. P., Lambert, A., & Robertson, W. R. (1988) · Journal of Endocrinology · doi:10.1677/joe.0.1190365 · Cited by 45
Amiodarone-induced thyrotoxicosis suggestive of thyroid damage
Lambert, M., Unger, J., Nayer, P. D., Brohet, C., & Gangji, D. (1990) · Journal of Endocrinological Investigation · doi:10.1007/bf03348618 · Cited by 26
Painful Autoimmune Thyroiditis Occurring on Amiodarone Therapy
Guðbjörnsson, B., Kristinsson, Á., Geirsson, G., & Hreiðarsson, Á. B. (1987) · Acta Medica Scandinavica · doi:10.1111/j.0954-6820.1987.tb01271.x · Cited by 19
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Perchlorate and the Thyroid Gland
Wolff, J. (1998) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01350-4 · Cited by 590
The Effects of Amiodarone on the Thyroid
Martino, E., Bartalena, L., Bogazzi, F., & Braverman, L. E. (2001) · Endocrine Reviews · doi:10.1210/edrv.22.2.0427 · Cited by 559
Self-citationBasaria, S. S., & Cooper, D. S. (2005) · The American Journal of Medicine · doi:10.1016/j.amjmed.2004.11.028 · Cited by 341
Iodine Excess and Hyperthyroidism
Roti, E., & Uberti, E. C. D. (2001) · Thyroid · doi:10.1089/105072501300176453 · Cited by 288
Metadata
- Authors
- Chiovato, L., Martino, E., Tonacchera, M., Santini, F., Lapi, P., Mammoli, C., Braverman, L. E., & Pinchera, A.
- Affiliations
- University of Pisa (IT)
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 1994-05
- Volume
- 134
- Issue
- 5
- Pages
- 2277-2282
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- OpenAlex
- W2087205488
- Cited by
- 107
- References
- 16
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 4 · 2021: 3 · 2020: 4 · 2019: 4 · 2018: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 3 · 2013: 3 · 2012: 5
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- National Institutes of Health (7r01dk018919-24)
- National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK DK-18919)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- amiodarone, cytotoxicity, thyroid cells, FRTL-5 cells, iodide organification, methimazole, thyroiditis, iodine-containing drugs, antiarrhythmic drugs, thyroid dysfunction, sodium diatrizoate, potassium iodide, chromium-51
- MeSH terms
- Amiodarone, Animals, Cell Division, Cell Line, Cell Survival, Cells, Cultured, Chromium Radioisotopes, Diatrizoate, DNA, Cricetinae, Humans, Iodides, Methimazole, Potassium Iodide, Thyroid Gland, Thyrotropin, CHO Cells, Rats
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