Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria

Spaniol, Markus; Bracher, Roswitha; Ha, Hui Riem; Folláth, Ferenc; Krähenbühl, Stephan

doi:10.1016/s0168-8278(01)00189-1

Cited by 111 publications

(78 citation statements)

References 23 publications

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“…As has been shown for amiodarone, 5 benzarone and benzbromarone also inhibited the formation of acid-soluble ␤-oxidation products in a dose-dependent manner (see Table 2). The corresponding IC 50 values were 34 mol/L for amiodarone, 34 mol/L for benzarone, and 2 mol/L for benzbromarone.…”

Section: Mitochondrial Membrane Potential As Shown Insupporting

confidence: 74%

“…Experiments were performed as previously described 22 with the modifications described by Spaniol et al 5 Ketone body formation by liver mitochondria was measured in the presence of an acetyl-CoA-generating system using freeze-thawed mitochondria according to Chapman et al 23 with the modifications described by Spaniol et al 5 The supernatants of the incubations were analyzed for acetoacetate according to Olsen 24 , using an enzyme-catalyzed reaction inducing changes in the concentration of ␤-nicotinamide adenine dinucleotide.…”

Section: Oxygen Uptakementioning

confidence: 99%

“…It inhibits enzyme complexes of the electron transport chain, impairs ␤-oxidation, and uncouples oxidative phosphorylation. [4][5][6] Benzbromarone is another benzofuran derivative acting as an uricosuric agent by reducing the proximal tubular reabsorption of uric acid. 7 Benzarone is a nonhalogenated benzbromarone derivative used for the treatment of venous vascular disorders.…”

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confidence: 99%

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Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

et al. 2005

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Treatment with benzarone or benzbromarone can be associated with hepatic injury. Both drugs share structural similarities with amiodarone, a well-known mitochondrial toxin. Therefore, we investigated the hepatotoxicity of benzarone and benzbromarone as well as the analogues benzofuran and 2-butylbenzofuran. In isolated rat hepatocytes, amiodarone, benzarone, and benzbromarone (20 mol/L) decreased mitochondrial membrane potential by 23%, 54% or 81%, respectively. Benzofuran and 2-butylbenzofuran had no effect up to 100 mol/L. In isolated rat liver mitochondria, amiodarone, benzarone, and benzbromarone, but not benzofuran, decreased state 3 oxidation and respiratory control ratios for L-glutamate (50% decrease of respiratory control ratio at [mol/L]: amiodarone, 12.9; benzarone, 10.8; benzbromarone, <1). Amiodarone, benzarone, and benzbromarone, but not benzofuran, also uncoupled oxidative phosphorylation. Mitochondrial ␤-oxidation was decreased by 71%, 87%, and 58% with 100 mol/L amiodarone or benzarone and 50 mol/L benzbromarone, respectively, but was unaffected by benzofuran, whereas ketogenesis was not affected. 2-Butylbenzofuran weakly inhibited state 3 oxidation and ␤-oxidation only at 100 mol/L. In the presence of 100 mol/L amiodarone, benzarone or benzbromarone, reactive oxygen species production was increased, mitochondrial leakage of cytochrome c was induced in HepG2 cells, and permeability transition was induced in isolated rat liver mitochondria. At the same concentrations, amiodarone, benzarone, and benzbromarone induced apoptosis and necrosis of isolated rat hepatocytes. In conclusion, hepatotoxicity associated with amiodarone, benzarone, and benzbromarone can at least in part be explained by their mitochondrial toxicity and the subsequent induction of apoptosis and necrosis. Side chains attached to the furan moiety are necessary for rendering benzofuran hepatotoxic.

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Section: Mitochondrial Membrane Potential As Shown Insupporting

confidence: 74%

Section: Oxygen Uptakementioning

confidence: 99%

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confidence: 99%

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Mechanisms of benzarone and benzbromarone-induced hepatic toxicity

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“…AMD consists 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). [185], and analysis of the chemical moieties within amiodarone responsible for mitochondrial toxicity indicates that the benzofuran structure is responsible for mitochondrial toxicity of AMD and the presence of iodine is not essential for this function. [185].…”

Section: Amiodarone Hepatotoxicitymentioning

confidence: 99%

“…[185], and analysis of the chemical moieties within amiodarone responsible for mitochondrial toxicity indicates that the benzofuran structure is responsible for mitochondrial toxicity of AMD and the presence of iodine is not essential for this function. [185]. Amiodarone was found to have significant detrimental effects on mitochondrial function and liver injury in an in vivo mouse model.…”

Section: Amiodarone Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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