Mechanisms of benzarone and benzbromarone-induced hepatic toxicity.
Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 micromol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 micromol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [micromol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial beta-oxidation was decreased by 71%, 87%, and 58% with 100 micromol/L amiodarone or benzarone and 50 micromol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and beta-oxidation only at 100 micromol/L. In the presence of 100 micromol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.
Kaufmann
Priska
P
Departments of Clinical Pharmacology & Toxicology and Research, University Hospital Basel, CH-4031 Basel, Switzerland.
Török
Michael
M
Hänni
Anya
A
Roberts
Paul
P
Gasser
Rodolfo
R
Krähenbühl
Stephan
S
D000638:Amiodarone / Q000737:chemistry / Q000506:poisoning; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001553:Benzbromarone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000506:poisoning*; D001572:Benzofurans / Q000737:chemistry / Q000506:poisoning; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D007657:Ketone Bodies / Q000096:biosynthesis; D008099:Liver / Q000187:drug effects*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008930:Mitochondria, Liver / Q000502:physiology; D008933:Mitochondrial Swelling / Q000187:drug effects; D015394:Molecular Structure; D009336:Necrosis; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D001572:Benzofurans; D007657:Ketone Bodies; D017382:Reactive Oxygen Species; C004528:benzarone; D001553:Benzbromarone; D000638:Amiodarone