Amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
Amiodarone has been shown to produce microvesicular steatosis of the liver in some recipients. We have determined the effects of amiodarone on the mitochondrial oxidation of fatty acids in mice. In vitro, the formation of 14C-acid-soluble beta-oxidation products from [U-14C]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125 microM amiodarone and by 94% in the presence of 125 microM N-desethylamiodarone. Inhibition due to 100 or 150 microM amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15 microM rotenone. In vivo, exhalation of [14C]CO2 from [U-14C]palmitic acid was decreased by 31, 40, 58 and 78%, respectively, in mice receiving 19, 25, 50 and 100 mg.kg-1 of amiodarone hydrochloride 1 hr before the administration of [U-14C]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [14C]CO2 from [1-14C]palmitic acid, [1-14C]octanoic acid or [1-14C]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [14C]CO2 from [1-14C]palmitic acid was normal between 6 and 9 hr after administration of 100 mg.kg-1 of amiodarone hydrochloride, but was still inhibited by 71 and 37%, 24 and 48 hr after 600 mg.kg-1. Twenty four hours after the latter dose of amiodarone, hepatic triglycerides were increased by 150%, and there was microvesicular steatosis of the liver. We conclude that amiodarone inhibits the mitochondrial beta-oxidation of fatty acids and produces microvesicular steatosis of the liver in mice.
Fromenty
B
B
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U24), Hôpital Beaujon, Clichy, France.
Fisch
C
C
Labbe
G
G
Degott
C
C
Deschamps
D
D
Berson
A
A
Letteron
P
P
Pessayre
D
D
D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002250:Carbon Radioisotopes; D004305:Dose-Response Relationship, Drug; D005218:Fat Necrosis / Q000139:chemically induced*; D005227:Fatty Acids / Q000378:metabolism*; D007657:Ketone Bodies / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects
D002250:Carbon Radioisotopes; D005227:Fatty Acids; D007657:Ketone Bodies; D002245:Carbon Dioxide; D000638:Amiodarone