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Amiodarone-induced cytotoxicity: Link to mitochondrial dysfunction and labile iron involvement

Domenii publicaţii > Ştiinţe medicale + Tipuri publicaţii > Articol în volumul unei conferinţe

Autori: Nicolescu A.C., Hill B.C., Brien J.F., Racz W.J., Massey T.E

Editorial: Chem. Res. Toxicol., 19(12), p.1684, 2006.


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 prodn. were analyzed by ESR spectroscopy using the spin-trapping probes TEMPO and DMPO. AM cytotoxicity in HPL1A cells was concn.- and time-dependent. The free radical reducing activity of HPL1A cells was decreased two-fold following exposure to low AM concns. (5-10 mM). 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. Addnl., in the presence of ethanol (a hydrogen atom donor), AM increased Fe2+-induced free radical prodn. 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.

Cuvinte cheie: Amiodarone; Free Radicals; Oxidative Stress; Cytotoxicity