Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration

Serviddio, Gaetano; Bellanti, Francesco; Giudetti, Anna Maria; Gnoni, Gabriele V.; Capitanio, Nazzareno; Tamborra, Rosanna; Romano, Antonino Davide; Quinto, Maurizio; Blonda, Maria; Vendemiale, Gianluigi; Altomare, Emanuele

doi:10.1016/j.freeradbiomed.2011.09.004

Cited by 81 publications

(48 citation statements)

References 43 publications

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“…Additionally, mitochondrial dysfunction leads to excessive lipids in the liver and may promote the formation of reactive oxygen species, leading to lipid peroxidation, inflammation, and fibrosis [8].…”

Section: Introductionmentioning

confidence: 99%

Early hepatic insult in the offspring of obese maternal mice

et al. 2015

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We hypothesized that the maternal obesity initiates metabolic disorders associated with oxidative stress in the liver of offspring since early life. Mouse's mothers were assigned into 2 groups according to the diet offered (n = 10 per group): standard chow (SC) or high-fat diet (HF). The results revealed that HF offspring had an increase in body mass at day 10 (+25%, P < .05) and in glucose levels (+25%, P < .0001). Hepatic triacylglycerol was increased in HF offspring at day 1 and day 10 compared with SC offspring (+30%, P < .01 and +40%, P < .01) as was hepatic steatosis (+110%, P < .001; +145%, P < .0001). Fatty acid synthase was increased in HF offspring at day 1 (+450%, P < .01) and peroxisome proliferator activator receptor-γ was elevated at day 1 and day 10 (+140%, P < .01; +2741%, P < .01). Peroxisome proliferator activator receptor-α was diminished in HF offspring at day 10 compared with SC offspring (-100%, P < .01). Moreover, carnitine palmitoyl-CoA transferase-1 was decreased in HF offspring at day 1 and day 10 (-80%, P < .01; -60%, P < .05). In the HF offspring (compared with the SC offspring), the catalase and the superoxide dismutase were significantly lower in both days 1 and 10 (P < .05). In 10-day-old offspring, glutathione peroxidase 1 and glutathione reductase were lower in HF offspring than in SC offspring (P < .0001). Our findings suggest that the maternal obesity in mice induces an early oxidative dysfunction coupled with hepatic steatosis and might contribute to progressive liver injury later in life.

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Section: Introductionmentioning

confidence: 99%

Early hepatic insult in the offspring of obese maternal mice

et al. 2015

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“…In theory, dronedarone is supposed to have limited hepatotoxicty compared to amiodarone [25]. Although prior studies have not shown any difference compared to amiodarone [17], they are limited due to the relatively short follow-up.…”

Section: Discussionmentioning

confidence: 98%

Efficacy and tolerability of dronedarone for patients with atrial fibrillation

Teme

Goldberger²

2013

Cardiol J

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“…In humans exposed to amiodarone, nerve conduction abnormalities vary from a predominant axonopathy, with reduced amplitudes of evoked responses, to prominent conduction slowing suggesting demyelination, to a mixed picture [1,2,7]. Inhibition of Complex 1 of respiratory chain and altered folate metabolism were proposed as one possible mechanism for toxicity [15]. Santoro et al [16] described electrophysiologically acute demyelination with CB at day 3 after amiodarone endoneurial injection into rat tibial nerves, suggesting a direct toxic effect on motor axons related to different drug concentrations, due to variable efficacy and vulnerability of blood-nerve barrier leading to different concentration in the nerves.…”

Section: Discussionmentioning

confidence: 99%

Amiodarone neurotoxicity: the other side of the medal

2014

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AbstractThe efficacy of amiodarone is tempered by its toxicity, with 50% of long-term users discontinuing the drug. The non-cardiac side effects of amiodarone may involve central and peripheral nervous system. We studied two patients treated with amiodarone for 46 and 15 months respectively. Both patients exhibited progressive distal extremity weakness, impaired perception, loss of deep reflexes. Electrophysiology identified a widespread, sensorimotor polyneuropathy with features of axonal loss and demyelination. Visual evoked potentials (VEPs) showed prolonged P100 latency bilaterally in absence of visual symptoms or brain magnetic resonance imaging (MRI) abnormalities. Extensive laboratory examinations excluded known causes of peripheral neuropathies. At 21 months after amiodarone withdrawal, P100 latency of case 1 VEPs returned to normal, whereas polyneuropathy continued to progress. In the second patient neuropathy has worsened similarly over 2 years whereas P100 latency of VEPs recovered to normal within 7 months after withdrawal of amiodarone. These findings may suggest different mechanisms of toxicity, which could be due to amiodarone pharmacokinetic and its metabolite effects on the peripheral nerves, as opposed to the optic nerve. We emphasize that use of amiodarone needs monitoring of patients at risk of development side effects.

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Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration

Cited by 81 publications

References 43 publications

Early hepatic insult in the offspring of obese maternal mice

Early hepatic insult in the offspring of obese maternal mice

Efficacy and tolerability of dronedarone for patients with atrial fibrillation

Amiodarone neurotoxicity: the other side of the medal

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