Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria

Background: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted wi th 2 iodines and a diethyl-ethanolamine side chain (ring B). Aim: To find out which part of amiodarone is responsible for mitochondrial toxicity. Methods: Amiodarone, ring A and B without the ethanolamine side-chain and i odines (B0), ring A and B with iodines but no ethanolamine (B2), ring B wit h 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodi nes (D2) were studied. Results: In freshly isolated rat liver mitochondria, amiodarone inhibited s tate 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B 2 more potent than B0. C1 and D2 showed no significant mitochondrial toxici ty. 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 amioda rone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. Conclusions: Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylat ion, and inhibit complexes I, II and III, and beta -oxidation. The benzofur an structure is responsible for mitochondrial toxicity of amiodarone and th e presence of iodine is not essential. (C) 2001 European Association for th e Study of the Liver. Published by Elsevier Science B.V. All rights reserve d.