Spaniol M, Bracher R, Ha H R, Follath F, Krähenbühl S
Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
J Hepatol. 2001 Nov;35(5):628-36. doi: 10.1016/s0168-8278(01)00189-1.
Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B).
To find out which part of amiodarone is responsible for mitochondrial toxicity.
Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied.
In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected.
Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.
胺碘酮是一种著名的线粒体毒素，由一个苯并呋喃环（A环）与一个对羟基苯结构相连组成，该对羟基苯结构被两个碘原子取代，并带有一个二乙氨基乙醇胺侧链（B环）。
确定胺碘酮的哪一部分导致线粒体毒性。
研究了胺碘酮、不含乙醇胺侧链和碘原子的A环和B环（B0）、含碘原子但不含乙醇胺的A环和B环（B2）、含一个碘原子且不含乙醇胺的B环（C1）以及含乙醇胺和两个碘原子的B环（D2）。
在新鲜分离的大鼠肝线粒体中，胺碘酮抑制状态3下谷氨酸和棕榈酰辅酶A的氧化，并降低呼吸控制率。B0和B2比胺碘酮是更强效的抑制剂，且B2比B0更强效。C1和D2未显示出明显的线粒体毒性。线粒体被破坏后，胺碘酮、B0和B2抑制线粒体氧化酶和电子传递链复合物，而C1和D2未显示出抑制作用。β-氧化受到胺碘酮、B0和B2的强烈抑制，但不受C1或D2的抑制。生酮作用几乎未受影响。
胺碘酮及B0和B2是氧化磷酸化的解偶联剂，抑制复合物I、II和III以及β-氧化。苯并呋喃结构是胺碘酮线粒体毒性的原因，碘的存在并非必需。
