Mechanisms of Phenytoin‐Induced Toxicity in Freshly Isolated Rat Hepatocytes and the Protective Effects of Taurine and/or Melatonin

Eghbal, Mohammad Ali; Taziki, Shohreh; Sattari, Mohammad

doi:10.1002/jbt.21542

Cited by 27 publications

(30 citation statements)

References 44 publications

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“…Melatonin significantly delayed disease onset and neurological deterioration; its effects were explained by an inhibition of Rip2/caspase-1 pathway activation, by the release of mitochondrial cytochrome c, and by a decreased overexpression and activation of caspase-3 (Zhang et al, 2013). In hepatocytes, melatonin normalized the levels of ROS formation, intracellular reduced glutathione, cellular oxidized glutathione, lipid peroxidation, and mitochondrial depolarization induced by the antiepileptic drug phenytoin (Eghbal et al, 2014). In smooth muscle cells, aging induced a partial mitochondrial depolarization in resting conditions and reduced the depolarizing response to cellular stimulation, and melatonin treatment prevented all these changes (Martin-Cano et al, 2014).…”

Section: Melatonin and Mitochondriamentioning

confidence: 96%

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

González¹,

Santofimia-Castaã'o²,

Salido³

2015

Turk J Biol

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Melatonin, a derivative of the amino acid tryptophan, was initially thought to be mainly produced and secreted by the pineal gland; with time, it was also found in other tissues and organs, and even in plants. Since its discovery, the study of the role of the indole in cellular homeostasis has generated impressive data, which have led researchers to a common idea regarding the positive actions of melatonin in health. The uncontrolled production of free radicals in cellular systems leads to the situation termed oxidative stress, which has been signaled as the basis of disease and aging. In the exocrine pancreas, as in other parts of the body, a daily confrontation takes place against oxidative stress. The major signaling mechanisms controlling the physiology of the gland are affected under this situation. Because a love-hate relationship involving mitochondria and oxidative stress has been considered the basis of disease, any physiological regulator that sets hands on the system as a pacemaker will be determinant for the health's fate. Here we present an overview of the recent findings regarding the protective role of melatonin on the function of the exocrine pancreas, paying attention to the role of Ca2+ signaling and the involvement of mitochondria.

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Section: Melatonin and Mitochondriamentioning

confidence: 96%

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

González¹,

Santofimia-Castaã'o²,

Salido³

2015

Turk J Biol

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“…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%

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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“…ROS in the liver is generated both enzymatically or non-enzymatically in the mitochondria of nonphagocytic cells [74], but phagocytic cells like macrophages and neutrophils also produce ROS via the cytochrome P450 enzymes (CYP450) [75]. Oxidative stress is involved in most kinds of acute and chronic liver diseases even in drug/xenobiotics associated hepatic injuries [72,76].…”

Section: Oxidative Stress and Liver Diseasementioning

confidence: 99%

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

Ahmadian

Pennefather

Eftekhari

et al. 2016

Expert Review of Gastroenterology & Hepatology

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The current review aimed to outline the functions of the renin angiotensin system (RAS) in the context of the oxidative stress-associated liver disease. Areas covered: Angiotensin II (Ang II) as the major effector peptide of the RAS is a pro-oxidant and fibrogenic cytokine. Mechanistically, NADPH oxidase (NOX) is a multicomponent enzyme complex that is able to generate reactive oxygen species (ROS) as a downstream signaling pathway of Ang II which is expressed in liver. Ang II has a detrimental role in the pathogenesis of chronic liver disease through possessing pro-oxidant, fibrogenic, and pro-inflammatory impact in the liver. The alternative axis (ACE2/Ang(1-7)/mas) of the RAS serves as an anti-inflammatory, antioxidant and anti-fibrotic component of the RAS. Expert commentary: In summary, the use of alternative axis inhibitors accompanying with ACE2/ Ang(1-7)/mas axis activation is a promising new strategy serving as a novel therapeutic option to prevent and treat chronic liver diseases.

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Mechanisms of Phenytoin‐Induced Toxicity in Freshly Isolated Rat Hepatocytes and the Protective Effects of Taurine and/or Melatonin

Cited by 27 publications

References 44 publications

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

Melatonin, mitochondria, and Ca2+ homeostasis in the exocrine pancreas: an overview

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

Role of renin-angiotensin system in liver diseases: an outline on the potential therapeutic points of intervention

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