Fromenty B, Fisch C, Labbe G, Degott C, Deschamps D, Berson A, Letteron P, Pessayre D
Unité de Recherches de Physiopathologie Hépatique (Institut National de la Santé et de la Recherche Médicale U24), Hôpital Beaujon, Clichy, France.
J Pharmacol Exp Ther. 1990 Dec;255(3):1371-6.
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.
已证实胺碘酮在一些接受者中可导致肝脏微泡性脂肪变性。我们测定了胺碘酮对小鼠脂肪酸线粒体氧化的影响。在体外，125μM胺碘酮存在时，小鼠肝脏线粒体由[U-14C]棕榈酸生成14C-酸溶性β-氧化产物的量减少了92%，125μM去乙基胺碘酮存在时减少了94%。100或150μM胺碘酮所致的抑制在5mM乙酰乙酸存在时持续存在，而乙酰乙酸可完全解除15μM鱼藤酮所致的抑制。在体内，在给予[U-14C]棕榈酸前1小时接受19、25、50和100mg·kg-1盐酸胺碘酮的小鼠中，[U-14C]棕榈酸呼出的[14C]CO2分别减少了31%、40%、58%和78%。给予100mg·kg-1 1小时后，[1-14C]棕榈酸、[1-14C]辛酸或[1-14C]丁酸呼出的[14C]CO2分别减少了78%、72%和53%。给予100mg·kg-1盐酸胺碘酮后6至9小时，[1-14C]棕榈酸呼出的[14C]CO2正常，但给予600mg·kg-1后24和48小时仍分别被抑制71%和37%。给予后一剂胺碘酮24小时后，肝脏甘油三酯增加了150%，出现了肝脏微泡性脂肪变性。我们得出结论，胺碘酮抑制脂肪酸的线粒体β-氧化并在小鼠中产生肝脏微泡性脂肪变性。
