title: Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles.
abstract: BACKGROUND
  Amiodarone, a potent antiarrhythmic, iodine-containing agent, is a highly active oxidant exerting cytotoxic effects on thyrocytes at pharmacological concentrations. Patients receiving amiodarone usually remain euthyroid, but occasionally develop thyroid dysfunction. Although there is a general consensus that amiodarone-associated hypothyroidism is iodine induced, the destructive mechanism of thyroid follicles in amiodarone-induced thyrotoxicosis remains unknown.
  
  
  OBJECTIVE
  To elucidate the mechanism by which amiodarone elicits thyroid dysfunction.
  
  
  METHODS
  Human thyroid follicles were cultured with thyroid-stimulating hormone (TSH) and amiodarone at therapeutic (1-2 microM) and pharmacological (10-20 microM) concentrations, and the drug-induced effect on whole human gene expression was analyzed by cDNA microarray. Microarray data were confirmed by real-time PCR and Western blot.
  
  
  RESULTS
  Amiodarone at 1-2 muM decreased the expression level of the sodium-iodide symporter (NIS) to nearly half, but did not affect genes participating in thyroid hormonogenesis (thyroid peroxidase, thyroglobulin, pendrin, and NADPH oxidase). Higher concentrations (10-20 microM) decreased the expression of all these genes, accompanied by increased expression of antioxidant proteins such as heme oxygenase 1 and ferritin. When thyroid follicles obtained from a patient with Graves' disease who had been treated with amiodarone were cultured in amiodarone-free medium, TSH-induced thyroid function was intact, suggesting that amiodarone at a maintenance dose did not elicit any cytotoxic effect on thyrocytes. The ultrastructural features of cultured thyroid follicles were compatible with these in vitro findings.
  
  
  CONCLUSIONS
  These in vitro and ex vivo findings suggest that patients taking maintenance doses of amiodarone usually remain euthyroid, probably due to escape from the Wolff-Chaikoff effect mediated by decreased expression of NIS mRNA. Further, amiodarone is not cytotoxic for thyrocytes at therapeutic concentrations but elicits cytotoxicity through oxidant activity at supraphysiological concentrations. We speculate that when amiodarone-induced prooxidant activity somehow exceeds the endogenous antioxidant capacity, the thyroid follicles will be destroyed and amiodarone-induced destructive thyrotoxicosis may develop.
authors.affiliation: Thyroid Disease Institute, Kanaji Hospital, Tokyo, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Yamazaki
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Mitsuhashi
authors.forename: Emiko
authors.initials: E
authors.lastname: Yamada
authors.forename: Tetsu
authors.initials: T
authors.lastname: Yamada
authors.forename: Seiichi
authors.initials: S
authors.lastname: Kosaka
authors.forename: Kazue
authors.initials: K
authors.lastname: Takano
authors.forename: Takao
authors.initials: T
authors.lastname: Obara
authors.forename: Kanji
authors.initials: K
authors.lastname: Sato
mesh_terms: D000638:Amiodarone / Q000494:pharmacology* / Q000627:therapeutic use; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000975:Antioxidants / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005293:Ferritins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006111:Graves Disease / Q000378:metabolism / Q000473:pathology; D006333:Heart Failure / Q000188:drug therapy; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007454:Iodides / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013610:Tachycardia / Q000188:drug therapy; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D000099209:Sodium-Iodide Symporters
chemical_list: D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D005293:Ferritins; D051547:Heme Oxygenase-1; D007454:Iodides; D012333:RNA, Messenger; D027981:Symporters; D000099209:Sodium-Iodide Symporters; C496541:HMOX1 protein, human