Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives.
The aim of this work was to compare hepatocellular toxicity and pharmacological activity of amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran; B2-O-Et-N-diethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamiodarone (B2-O-Et-NH-ethyl), di-N-desethylamiodarone (B2-O-Et-NH(2)), and (2-butyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)-methanone (B2) carrying an ethanol side chain [(2-butylbenzofuran-3-yl)-[4-(2-hydroxyethoxy)-3,5-diiodophenyl]-methanone; B2-O-Et-OH]. In addition, five amiodarone analogs were investigated, namely, N-dimethylamiodarone (B2-O-Et-N-dimethyl), N-dipropylamiodarone (B2-O-Et-N-dipropyl), B2-O-carrying an acetate side chain [[4-(2-butyl-benzofuran-3-carbonyl)-2,6-diiodophenyl]-acetic acid; B2-O-acetate], B2-O-Et carrying an propionamide side chain (B2-O-Et-propionamide), and B2-O carrying an ethyl side chain [(2-butylbenzofuran-3-yl)-(4-ethoxy-3,5-diiodophenyl)-methanone; B2-O-Et]. A concentration-dependent increase in lactate dehydrogenase leakage from HepG2 cells and isolated rat hepatocytes was observed in the presence of amiodarone and of most analogs, confirming their hepatocellular toxicity. Using freshly isolated rat liver mitochondria, amiodarone and most analogs showed a dose-dependent toxicity on the respiratory chain and on beta-oxidation, significantly reducing the respiratory control ratio and oxidation of palmitate, respectively. The reactive oxygen species concentration in hepatocytes increased time-dependently, and apoptotic/necrotic cell populations were identified using flow cytometry and annexin V/propidium iodide staining. The effect of the three least toxic amiodarone analogs on the human ether-a-go-go-related gene (hERG) channel was compared with amiodarone. Amiodarone, B2-O-acetate, and B2-O-Et-N-dipropyl (each 10 microM) significantly reduced the hERG tail current amplitude, whereas 10 microM B2-O-Et displayed no detectable effect on hERG outward potassium currents. In conclusion, three amiodarone analogs (B2-O-Et-N-dipropyl, B2-O-acetate, and B2-O-Et) showed a lower hepatocellular toxicity profile than amiodarone, and two of these analogs (B2-O-Et-N-dipropyl and B2-O-acetate) retained hERG channel interaction capacity, suggesting that amiodarone analogs with class III antiarrhythmic activity and lower hepatic toxicity could be developed.
Waldhauser
Katri Maria
KM
Division of Clinical Pharmacology and Toxicology, Department of Research, University Hospital Basel, Switzerland.
Török
Michael
M
Ha
Huy-Riem
HR
Thomet
Urs
U
Konrad
Daniel
D
Brecht
Karin
K
Follath
Ferenc
F
Krähenbühl
Stephan
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000638:Amiodarone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D017304:Annexin A5; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis / Q000494:pharmacology / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D016466:CHO Cells; D002460:Cell Line; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D055598:Chemical Phenomena; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002627:Chemistry, Physical; D004396:Coloring Agents; D006224:Cricetinae; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000473:pathology; D009336:Necrosis; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011419:Propidium; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012995:Solubility
D017304:Annexin A5; D000889:Anti-Arrhythmia Agents; D004396:Coloring Agents; D051638:Ether-A-Go-Go Potassium Channels; D007202:Indicators and Reagents; C496884:KCNH1 protein, human; D026902:Potassium Channel Blockers; D017382:Reactive Oxygen Species; D011419:Propidium; D000255:Adenosine Triphosphate; D000638:Amiodarone