AMIODARONE INDUCES A DIFFERENT PATTERN OF ULTRASTRUCTURAL CHANGE IN THE THYROID TO IODINE EXCESS ALONE IN BOTH THE BB W RAT AND THE WISTAR RAT/

Amiodarone (AMD)-induced toxicity can be a life-threatening complicati on which limits the use of amiodarone as an anti-arrhythmic agent. The aim of the present study was to determine the nature of AMD toxicity by comparing ultrastructural changes induced by AMD and equivalent amo unts of iodide in two animal models, the Wistar and the autoimmune BB/ W rat. Rats were divided into control (water), AMD- (30 mg AMD/kg) or iodide-treated (10 mg/kg) groups. Thyroids were removed at 15 weeks an d processed for electron microscopy. We found that AMD induced specifi c ultrastructural changes of thyroid cytotoxicity in both rat models, which were distinct compared with changes induced by excess iodide alo ne. Specific changes included marked distortion of thyroid architectur e, evidence of necrosis and apoptosis, inclusion bodies, lipofuscinoge nesis and markedly dilated endoplasmic reticulum (ER). Our data indica te that AMD is directly cytotoxic to the thyroid an effect mediated by disruption of subcellular organelle function. ER dilatation is sugges tive that AMD cytotoxicity may be mediated through disruption of the p rotein sorting pathways leading to a drug-induced form of ER storage d isease. The predilection of the thyroid to AMD may be explained by the additive effects of excess iodine and AMD drug toxicity on protein so rting pathways.