TOXI 38 |
| Amiodarone (AM) is an effective drug for the treatment of life-threatening cardiac dysrhythmias. However, AM can produce serious hepatic and pulmonary toxicities. Several hypotheses have been proposed for the mechanism of AM-induced cytotoxicity, including altered inflammatory mediator release, mitochondrial dysfunction, and free radical formation. We investigated the toxic susceptibility and mitochondrial activity of a human peripheral lung epithelial cell line (HPL1A) exposed to AM. The effects of AM on mitochondrial free radical reducing activity in isolated mitochondria, and on the free Fe2+-induced free radical production were analyzed by electron paramagnetic resonance spectroscopy using the spin-trapping probes TEMPO and DMPO. AM cytotoxicity in HPL1A cells was concentration- and time-dependent. The free radical reducing activity of HPL1A cells was decreased two-fold following exposure to low AM concentrations (5-10 µM). The cytoprotective agents, PBN and Trolox C®, had minimal effect on AM-induced cytotoxicity. Respiring mitochondria treated with AM had decreased free radical reducing activity. Additionally, in the presence of ethanol (a hydrogen atom donor), AM increased Fe2+-induced free radical production two-fold compared to control. These data demonstrate that AM targets mitochondrial complex I, and that AM can amplify free radical formation. Both these processes may be involved in the multifaceted mechanism of AM-induced cytotoxicity. (Supported by CIHR grant MOP-13257) |
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General Papers: Young Investigator Session
8:00 AM-12:00 PM, Tuesday, 12 September 2006 Moscone Center -- Room 308, Oral
Sci-Mix
Division of Chemical Toxicology |