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Am J Physiol Lung Cell Mol Physiol (April 9, 2004). doi:10.1152/ajplung.00434.2003
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Submitted on December 5, 2003
Accepted on March 25, 2004

Effects of metabolites and analogues of amiodarone on alveolar macrophages: structure-activity relationship

Daniela Quaglino1, Huy Riem Ha2, Elena Duner3, Daniela Bruttomesso4, Laurent Bigler5, Ferenc Follath2, Giuseppe Realdi3, Andrea Pettenazzo6, and Aldo Baritussio3*

1 Department of Biomedical Sciences, University of Modena and Reggio Emilia, Modena, Italy
2 Cardiovascular Therapy Research Laboratory, Department of Internal Medine, University Hospiatal of Zurich, Zurich, Switzerland
3 Clinica Medica 1, Department of Medical and Surgical Sciences, University of Padova, Padova, Italy
4 Malattia del Metabolismo, Department of Clinical Medicine, University of Padova, Padova, Italy
5 Institute of Organic Chemistry, University of Zurich, Zurich, Switzerland
6 Department of Pediatrics, University of Padova, Padova, Italy

* To whom correspondence should be addressed. E-mail: aldo.baritussio{at}unipd.it.

Amiodarone, an antiarrhythmic drug toxic towards the lung, is metabolized through sequential modifications of the diethylaminoethoxy group to mono-N-desethylamiodarone (MDEA), di-Ndesetylamiodarone (DDEA) and amiodarone-EtOH (B2-O-EtOH), whose effects on lung cells are unclear. To clarify this, we exposed rabbit alveolar macrophages to analogues 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 (SP-A), used as a tracer of the endocytic pathway. The substances studied included: MDEA, DDEA and B2-O-EtOH, analogues with different modifications of the diethylaminoethoxy group, fragments of the amiodarone molecule and the antiarrhythmic agents dronedarone (SR33589) and KB130015. We found the following: a) MDEA, DDEA and B2-O-EtOH rank in order of decreasing toxicity towards alveolar macrophages, indicating that dealkylation and deamination of the diethylaminoethoxy group represent important mechanisms of detoxification; b) dronedarone has greater and KB13001 has smaller toxicity than amiodarone towards alveolar macrophages; c) the benzofuran moiety, which is toxic to liver cells, is not directly toxic towards alveolar macrophages.




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