Cytotoxic interaction between amiodarone and desethylamiodarone in human peripheral lung epithelial cells. 2013

Fiona C Roth, and Jeanne E Mulder, and James F Brien, and Takashi Takahashi, and Thomas E Massey
Pharmacology and Toxicology Graduate Program, Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada K7L 3N6.

The potent and efficacious anti-dysrhythmic agent amiodarone (AM) can cause potentially life-threatening lung damage (amiodarone-induced pulmonary toxicity; AIPT), which is characterized by cell death in the lungs, followed by inflammation and fibrosis. AM's major metabolite, desethylamiodarone (DEA), has a greater toxic potency than AM and it has been suggested that DEA may act synergistically with AM to cause lung toxicity. The objective of this study was to determine the type of cytotoxic interaction between AM and DEA in HPL1A human peripheral lung epithelial cells. Cytotoxicity was measured by lactate dehydrogenase release. AM and DEA caused concentration-dependent cytotoxicity in HPL1A cells. The concentration of drug causing 50% cell death (LC50) and the Hill slope factor, which represents steepness of the concentration-cell death curve, were significantly different between AM and DEA (12.4μM and 1.98; 5.07μM and 5.43, for AM and DEA, respectively) indicating that they may induce cytotoxicity through different mechanisms. A combined concentration of 7.13μM AM plus DEA, equivalent to 41% of each compound's individual LC50 value, resulted in 50% cell death. Isobolographic analysis revealed this effect to be additive, although the combined concentrations were only slightly higher than the concentrations that defined the threshold of synergy (threshold of synergy=4.21±1.98μM AM plus 1.73±1.05μM DEA; experimental data point=5.06±0.47μM AM plus 2.07±0.47μM DEA). The cytotoxic interaction between AM and DEA may be clinically relevant in the development of AIPT.

UI MeSH Term Description Entries
D007770 L-Lactate Dehydrogenase A tetrameric enzyme that, along with the coenzyme NAD+, catalyzes the interconversion of LACTATE and PYRUVATE. In vertebrates, genes for three different subunits (LDH-A, LDH-B and LDH-C) exist. Lactate Dehydrogenase,Dehydrogenase, L-Lactate,Dehydrogenase, Lactate,L Lactate Dehydrogenase
D008168 Lung Either of the pair of organs occupying the cavity of the thorax that effect the aeration of the blood. Lungs
D002478 Cells, Cultured Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others. Cultured Cells,Cell, Cultured,Cultured Cell
D004357 Drug Synergism The action of a drug in promoting or enhancing the effectiveness of another drug. Drug Potentiation,Drug Augmentation,Augmentation, Drug,Augmentations, Drug,Drug Augmentations,Drug Potentiations,Drug Synergisms,Potentiation, Drug,Potentiations, Drug,Synergism, Drug,Synergisms, Drug
D004847 Epithelial Cells Cells that line the inner and outer surfaces of the body by forming cellular layers (EPITHELIUM) or masses. Epithelial cells lining the SKIN; the MOUTH; the NOSE; and the ANAL CANAL derive from ectoderm; those lining the RESPIRATORY SYSTEM and the DIGESTIVE SYSTEM derive from endoderm; others (CARDIOVASCULAR SYSTEM and LYMPHATIC SYSTEM) derive from mesoderm. Epithelial cells can be classified mainly by cell shape and function into squamous, glandular and transitional epithelial cells. Adenomatous Epithelial Cells,Columnar Glandular Epithelial Cells,Cuboidal Glandular Epithelial Cells,Glandular Epithelial Cells,Squamous Cells,Squamous Epithelial Cells,Transitional Epithelial Cells,Adenomatous Epithelial Cell,Cell, Adenomatous Epithelial,Cell, Epithelial,Cell, Glandular Epithelial,Cell, Squamous,Cell, Squamous Epithelial,Cell, Transitional Epithelial,Cells, Adenomatous Epithelial,Cells, Epithelial,Cells, Glandular Epithelial,Cells, Squamous,Cells, Squamous Epithelial,Cells, Transitional Epithelial,Epithelial Cell,Epithelial Cell, Adenomatous,Epithelial Cell, Glandular,Epithelial Cell, Squamous,Epithelial Cell, Transitional,Epithelial Cells, Adenomatous,Epithelial Cells, Glandular,Epithelial Cells, Squamous,Epithelial Cells, Transitional,Glandular Epithelial Cell,Squamous Cell,Squamous Epithelial Cell,Transitional Epithelial Cell
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000638 Amiodarone An antianginal and class III antiarrhythmic drug. It increases the duration of ventricular and atrial muscle action by inhibiting POTASSIUM CHANNELS and VOLTAGE-GATED SODIUM CHANNELS. There is a resulting decrease in heart rate and in vascular resistance. Amiobeta,Amiodarex,Amiodarona,Amiodarone Hydrochloride,Amiohexal,Aratac,Braxan,Corbionax,Cordarex,Cordarone,Kordaron,L-3428,Ortacrone,Rytmarone,SKF 33134-A,Tachydaron,Trangorex,Hydrochloride, Amiodarone,L 3428,L3428,SKF 33134 A,SKF 33134A
D015394 Molecular Structure The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. Structure, Molecular,Molecular Structures,Structures, Molecular
D016923 Cell Death The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. Death, Cell
D018675 Toxicity Tests An array of tests used to determine the toxicity of a substance to living systems. These include tests on clinical drugs, foods, and environmental pollutants. Tests, Toxicity,Test, Toxicity,Toxicity Test

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