title: Disruption of mitochondrial function and cellular ATP levels by amiodarone and N-desethylamiodarone in initiation of amiodarone-induced pulmonary cytotoxicity.
abstract: Amiodarone (AM), a potent antidysrhythmic agent, can cause potentially life-threatening pulmonary fibrosis. In the present investigation of mechanisms of initiation of AM lung toxicity, we found that 100 microM AM decreased mitochondrial membrane potential in intact hamster lung alveolar macrophages and preparations enriched in isolated alveolar type II cells and nonciliated bronchiolar epithelial (Clara) cells, following 2 h of incubation. This was followed by a drop in cellular ATP content (by 32--77%) at 4 to 6 h, and 30 to 55% loss of viability at 24 h. Supplementation of incubation media with 5.0 mM glucose or 2.0 mM niacin did not reduce AM-induced ATP depletion or cell death in macrophages, and the mitochondrial permeability transition inhibitor cyclosporin A (1.0 microM) did not affect AM cytotoxicity. At 50 microM, the AM metabolite N-desethylamiodarone (DEA) produced effects similar to those of AM, but more rapidly and extensively, with the Clara cell-enriched preparation being particularly susceptible. In isolated whole lung mitochondria, DEA was accumulated to a greater extent than AM. Both AM and DEA inhibited complex I- and complex II-supported respiration, but DEA inhibited complex II to a greater degree than AM. These results demonstrate that AM and DEA disrupt mitochondrial membrane potential prior to ATP depletion and subsequent lung cell death, that DEA is more potent than AM, and that the mitochondrial permeability transition is not involved in mitochondrial perturbation by AM. This suggests that AM- and DEA-induced perturbations of mitochondrial function may initiate AM-induced pulmonary toxicity.
authors.affiliation: Department of Pharmacology and Toxicology, Queen's University, Kingston, Ontario, Canada.
authors.forename: M W
authors.initials: MW
authors.lastname: Bolt
authors.forename: J W
authors.initials: JW
authors.lastname: Card
authors.forename: W J
authors.initials: WJ
authors.lastname: Racz
authors.forename: J F
authors.initials: JF
authors.lastname: Brien
authors.forename: T E
authors.initials: TE
authors.lastname: Massey
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000638:Amiodarone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008171:Lung Diseases / Q000139:chemically induced* / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008647:Mesocricetus; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D010101:Oxygen Consumption; D010539:Permeability; D011048:Polarography
chemical_list: D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; C036116:desethylamiodarone; D000638:Amiodarone