title: Endoplasmic reticulum stress as a novel mechanism in amiodarone-induced destructive thyroiditis.
abstract: BACKGROUND
  Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available; however, its use is limited by a serious side effect profile, including thyroiditis. The mechanisms underlying AMIO thyroid toxicity have been elusive; thus, identification of novel approaches in order to prevent thyroiditis is essential in patients treated with AMIO.
  
  
  OBJECTIVE
  Our aim was to evaluate whether AMIO treatment could induce endoplasmic reticulum (ER) stress in human thyroid cells and the possible implications of this effect in AMIO-induced destructive thyroiditis.
  
  
  RESULTS
  Here we report that AMIO, but not iodine, significantly induced the expression of ER stress markers including Ig heavy chain-binding protein (BiP), phosphoeukaryotic translation initiation factor 2α (eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO down-regulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced down-regulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1 cells and human primary thyrocytes with the chemical chaperone 4-phenylbutyric acid completely prevented the effect of AMIO on both ER stress induction and Tg down-regulation.
  
  
  CONCLUSIONS
  We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation, providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.
authors.affiliation: Division of Endocrinology (A.L., K.E.F., Y.T.) and Department of Surgery (W.B.I., R.O.), Icahn School of Medicine at Mt Sinai, New York, New York 10029; and James J. Peters Veterans Affairs Medical Center (Y.T.), Bronx, New York 10468.
authors.forename: Angela
authors.initials: A
authors.lastname: Lombardi
authors.forename: William Barlow
authors.initials: WB
authors.lastname: Inabnet
authors.forename: Randall
authors.initials: R
authors.lastname: Owen
authors.forename: Kaitlyn Ellen
authors.initials: KE
authors.lastname: Farenholtz
authors.forename: Yaron
authors.initials: Y
authors.lastname: Tomer
mesh_terms: D000638:Amiodarone / Q000009:adverse effects* / Q000494:pharmacology; D000889:Anti-Arrhythmia Agents / Q000009:adverse effects* / Q000494:pharmacology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071701:Regulatory Factor X Transcription Factors; D013954:Thyroglobulin / Q000235:genetics / Q000378:metabolism; D013961:Thyroid Gland / Q000187:drug effects* / Q000378:metabolism; D013966:Thyroiditis / Q000139:chemically induced* / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D000071717:X-Box Binding Protein 1
chemical_list: D000889:Anti-Arrhythmia Agents; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D015852:Eukaryotic Initiation Factor-2; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP; D013954:Thyroglobulin; D000638:Amiodarone