Aromatic antiepileptic drugs and mitochondrial toxicity: Effects on mitochondria isolated from rat liver

Santos, Neife Aparecida Guinaim dos; Medina, Wanessa Silva Garcia; Martins, Nádia Maria; Mingatto, Fábio Ermínio; Curti, Carlos; Santos, Antônio Cardozo dos

doi:10.1016/j.tiv.2008.03.004

Cited by 50 publications

(36 citation statements)

References 24 publications

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“…It is assumed that the accumulation of the arene oxide metabolites could be the responsible mechanism for the cellular damage caused by this drug (Bavdekar et al, 2004). Accumulation of arene oxide metabolite leads to direct mitochondrial toxicity, and also could result in immune response (Santos et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

Protective Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes

2013

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SUMMARY:Carbamazepine is widely used in a broad spectrum of psychiatric and neurological disorders. Idiosyncratic hepatotoxicity is a well-known adverse reaction associated with carbamazepine. Hepatotoxicity is rare, but a real concern when initiating therapy. It was found that oxidative stress is a potential mechanism for carbamazepine-induced hepatotoxicity. Present study evaluated the hepato protective role of taurine and melatonin against carbamazepine-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. Cells were treated with 400 µM carbamazepine, 1mM taurine, and 1mM melatonin. Cell death, reactive oxygen species formation, lipid peroxidation, and mitochondrial membrane depolarization were assessed as toxicity markers and the effects of taurine and melatonin administration on them were investigated. Our results showed that carbamazepine induced oxidative stress; increased ROS formation and lipid peroxidation products and also decreased mitochondrial membrane potential (∆Ψ m ). Carbamazepine caused a decrease in cellular glutathione content and an elevation in oxidized glutathione levels. Our investigation showed that preincubation of hepatocytes with taurine (1 mM) could alleviate oxidative damages induced by carbamazepine; melatonin was also a good antioxidant to protect hepatocytes against cytotoxicity induced by carbamazepine. It may be concluded that taurine and melatonin are effective antioxidants to prevent carbamazepine-induced hepatotoxicity. Following our findings, further studies are suggested on the antioxidant effects of taurine and melatonin in patients receiving carbamazepine.

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Section: Introductionmentioning

confidence: 99%

Protective Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes

2013

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“…Carbamazepine and phenytoin can both inhibit mitochondrial respiration [159, 170]and a study with carbamazepine in epileptic children who started new AED drug treatment showed significant reduction of ATP production [149] and mitochondrial respiration [159]. While investigating carbamazepine, phenytoin and phenobarbital effects on mitochondrial function in a murine hepatic microsomal system used to produce AED metabolites, it was found that mitochondrial membrane potential was also reduced [159].…”

Section: Anti-epileptic Drug Hepatotoxicitymentioning

confidence: 99%

Section: Anti-epileptic Drug Hepatotoxicitymentioning

confidence: 99%

“…While investigating carbamazepine, phenytoin and phenobarbital effects on mitochondrial function in a murine hepatic microsomal system used to produce AED metabolites, it was found that mitochondrial membrane potential was also reduced [159]. In the same study, the drugs also impaired Ca 2+ uptake/release [159]. An evaluation of the cytotoxic mechanisms of phenytoin in rat hepatocytes showed elevation in ROS formation, depletion of intracellular reduced glutathione, increase in cellular oxidized glutathione, enhancement of lipid peroxidation, and mitochondrial damage [180].…”

Section: Anti-epileptic Drug Hepatotoxicitymentioning

confidence: 99%

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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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“…33 Antiepileptic medications, including carbamazepine, may cause mitochondrial toxicity 34,35 and oxidative stress 36 after long-term use. The effects of acute carbamazepine toxicity on mitochondrial function are unknown.…”

Section: Figurementioning

confidence: 99%

Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose

Agulnik

Kelly²,

Bruccoleri³

et al. 2017

Pediatrics

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A 15-year-old female subject presented comatose, in respiratory failure and shock, after the intentional ingestion of ∼280 extended-release 200-mg carbamazepine tablets with a peak serum concentration of 138 µg/mL (583.74 µmol/L). The patient developed clinical seizures and an EEG pattern of stimulus-induced rhythmic, periodic, or ictal discharges, suggestive of significant cortical dysfunction. Due to the extremely high drug serum concentration and clinical instability, a combination of therapies was used, including lipid emulsion therapy, plasmapheresis, hemodialysis, continuous venovenous hemodiafiltration, and endoscopic intestinal decontamination. The patient’s elevated serum lactate level with a high mixed venous saturation suggested possible mitochondrial dysfunction, prompting treatment with barbiturate coma to reduce cerebral metabolic demand. The serum carbamazepine concentration declined steadily, with resolution of lactic acidosis, no long-term end-organ damage, and return to baseline neurologic function. The patient was eventually discharged in her usual state of health. In the laboratory, we demonstrated in vitro that the active metabolite of carbamazepine hyperpolarized the mitochondrial membrane potential, supporting the hypothesis that the drug caused mitochondrial dysfunction. We thus successfully treated a life-threatening carbamazepine overdose with a combination of modalities. Future studies are required to validate this aggressive approach. The occurrence of mitochondrial dysfunction must be confirmed in patients with carbamazepine toxicity and the need to treat it validated.

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Aromatic antiepileptic drugs and mitochondrial toxicity: Effects on mitochondria isolated from rat liver

Cited by 50 publications

References 24 publications

Protective Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes

Protective Role of Melatonin and Taurine Against Carbamazepine-induced Toxicity in Freshly Isolated Rat Hepatocytes

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

Combination Clearance Therapy and Barbiturate Coma for Severe Carbamazepine Overdose

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