Effects of metabolites and analogs of amiodarone on alveolar macrophages: structure-activity relationship.
Amiodarone, an antiarrhythmic drug toxic toward the lung, is metabolized through sequential modifications of the diethylaminoethoxy group to mono-N-desethylamiodarone (MDEA), di-N-desethylamiodarone (DDEA), and amiodarone-EtOH (B2-O-EtOH), whose effects on lung cells are unclear. To clarify this, we exposed rabbit alveolar macrophages to analogs with different modifications of the diethylaminoethoxy group and then searched for biochemical signs of cell damage, formation of vacuoles and inclusion bodies, and interference with the degradation of surfactant protein A, used as a tracer of the endocytic pathway. The substances studied included MDEA, DDEA, and B2-O-EtOH, analogs with different modifications of the diethylaminoethoxy group, fragments of the amiodarone molecule, and the antiarrhythmic agents dronedarone (SR-33589) and KB-130015. We found the following: 1). MDEA, DDEA, and B2-O-EtOH rank in order of decreasing toxicity toward alveolar macrophages, indicating that dealkylation and deamination of the diethylaminoethoxy group represent important mechanisms of detoxification; 2). dronedarone has greater, and KB-130015 has smaller, toxicity than amiodarone toward alveolar macrophages; and 3). the benzofuran moiety, which is toxic to liver cells, is not directly toxic toward alveolar macrophages.
Quaglino
Daniela
D
Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena.
Ha
Huy Riem
HR
Duner
Elena
E
Bruttomesso
Daniela
D
Bigler
Laurent
L
Follath
Ferenc
F
Realdi
Giuseppe
G
Pettenazzo
Andrea
A
Baritussio
Aldo
A
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001572:Benzofurans / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D000077764:Dronedarone; D007457:Iodine Radioisotopes; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000648:ultrastructure; D008854:Microscopy, Electron; D037662:Pulmonary Surfactant-Associated Protein A / Q000493:pharmacokinetics; D011817:Rabbits; D013329:Structure-Activity Relationship; D014132:Trachea
D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D007457:Iodine Radioisotopes; C446946:KB 130015; D037662:Pulmonary Surfactant-Associated Protein A; D000077764:Dronedarone; D000638:Amiodarone