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 C-14-acid-soluble beta-oxidation products from [U-C-14]palmitic acid by mouse liver mitochondria was decreased by 92% in the presence of 125-mu-M amiodarone and by 94% in the presence of 125-mu-M N-desethylamiodarone. Inhibition due to 100 or 150-mu-M amiodarone persisted in the presence of 5 mM acetoacetate, whereas acetoacetate totally relieved inhibition due to 15-mu-M rotenone. In vivo, exhalation of [C-14]CO2 from [U-C-14]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-C-14]palmitic acid. One hour after 100 mg.kg-1, the exhalation of [C-14]CO2 from [1-C-14]palmitic acid, [1-C-14]octanoic acid or [1-C-14]butyric acid was decreased by 78, 72 and 53%, respectively. Exhalation of [C-14]CO2 from [1-C-14]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 produce microvesicular steatosis of the liver in mice.