Amiodarone-induced lymphocyte toxicity and mitochondrial function.
Amiodarone is one of the most effective antiarrhythmic drugs available. However, its use is often limited by potentially life-threatening toxicities, including hepatotoxicity and pulmonary toxicity. We have used human lymphocytes as a system in which to study amiodarone-induced cytotoxicity. Using a tetrazolium dye reduction assay, we observed amiodarone-induced cytotoxicity with a lethal dose (LD)50 of 10.0 +/- 31.1 microM (mean +/- SD, n = 5) with a cellular concentration of 2.2 +/- 0.2 million/ml and of 55.5 and 39.2 microM with cellular concentrations of 8.9 and 7.2 million/ml, respectively, after only 2.75 h of drug exposure. Damage to mitochondria, but not other organelles, was observed with electron microscopy at an amiodarone concentration of 7.3 microM. Alterations in ATP synthesis and lactate dehydrogenase (LDH) release from cells had concentration-response curves similar to those for cytotoxicity. However, we did not observe extracellular accumulation of adenine nucleotides. These results suggest that amiodarone may have a direct toxic effect on mitochondria, beginning at < 10 microM, with membrane-damaging effects at higher drug concentrations.
Yasuda
S U
SU
Department of Pharmacology, Georgetown University Medical Center, Washington, D.C. 20007, USA.
Sausville
E A
EA
Hutchins
J B
JB
Kennedy
T
T
Woosley
R L
RL
D000241:Adenosine / Q000378:metabolism; D000328:Adult; D000638:Amiodarone / Q000494:pharmacology*; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure
D000889:Anti-Arrhythmia Agents; D007770:L-Lactate Dehydrogenase; D000241:Adenosine; D000638:Amiodarone