Studies on the in vitro cytotoxic effect of amiodarone

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.