Narges Abdoli

Mechanisms of the Statins Cytotoxicity in Freshly Isolated Rat Hepatocytes

Statins are potent drugs, used as lipid‐lowering agents in cardiovascular diseases. Hepatotoxicity is one of the serious adverse effects of statins, and the exact mechanism of hepatotoxicity is not yet clear. In this study, the cytotoxic effects of the most commonly used statins, that is, atorvastatin, lovastatin, and simvastatin toward isolated rat hepatocytes, were evaluated. Markers, such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, and the amount of reduced and oxidized glutathione in the statin‐treated hepatocytes, were investigated. It was found that the statins caused cytotoxicity toward rat hepatocytes dose dependently. An elevation in ROS formation, accompanied by a significant amount of lipid peroxidation and mitochondrial depolarization, was observed. Cellular glutathione reservoirs were decreased, and a significant amount of oxidized glutathione was formed. This study suggests that the adverse effect of statins toward hepatocytes is mediated through oxidative stress and the hepatocytes mitochondria play an important role in the statin‐induced toxicity.

Factors affecting drug-induced liver injury: antithyroid drugs as instances

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed.

An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs.

A comparison between the nephrotoxic profile of gentamicin and gentamicin nanoparticles in mice.

Aminoglycoside antibiotics are widely used against Gram‐negative infections. On the other hand, nephrotoxicity is a deleterious side effect associated with aminoglycoside therapy. Gentamicin is the most nephrotoxic aminoglycoside. Because of serious health complications ensue the nephrotoxicity induced by aminoglycosides, finding new therapeutic strategies against this problem has a great clinical value. This study has attempted to compare the nephrotoxic properties of gentamicin and a new nanosized formulation of this drug in a mice model. Animals were treated with gentamicin (100 mg/kg, i.p. for eight consecutive days) and nanogentamicin (100 mg/kg, i.p. for eight consecutive days). Blood urea nitrogen (BUN), plasma creatinine levels, and histopathological changes of kidney proximal tubule were monitored. It was found that gentamicin caused severe degeneration of kidney proximal tubule cells and an increase in serum creatinine and BUN. No severe injury was observed after nanogentamicin administration. This study proved that nanosized gentamicin is less nephrotoxic.

Effect of taurine on chronic and acute liver injury: Focus on blood and brain ammonia

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Paradoxical effect of methimazole on liver mitochondria: In vitro and in vivo.

Methimazole is the most frequently prescribed antithyroid agent. On the other hand, several cases of liver injury are attributed to this drug. The mechanism of methimazole-induced liver injury is obscure. Hepatocytes mitochondria seem to be a target for methimazole cytotoxicity. Current investigation aimed to evaluate the effects of methimazole on the hepatocytes mitochondria in different experimental models. In the in vivo model, methimazole (100, 200 and 400mg/kg, i.p) was administered to mice and liver mitochondria were isolated and assessed. In the in vitro experiments, intact isolated liver mitochondria were incubated with increasing methimazole concentrations (10μM-100mM). It was found that methimazole decreased liver mitochondrial ATP and glutathione, increased mitochondrial swelling, lipid peroxidation and reactive oxygen species (ROS), and collapsed mitochondrial membrane potential when administered to mice. Paradoxically, methimazole not only caused no significant injury toward isolated liver mitochondria in vitro but improved mitochondrial function and protected this organelle. The differences between two investigated models in the current study might be associated with drug bioactivation and reactive metabolites formation. These findings suggest mitochondrial dysfunction as a mechanism for methimazole-induced liver injury. Moreover, methimazole seems to be a novel mitochondrial protecting agent in vitro.

Protective Effects of N-acetylcysteine Against the Statins Cytotoxicity in Freshly Isolated Rat Hepatocytes

PURPOSE Hepatotoxicity is one of the most important side effects of the statins therapy as lipid-lowering agents. However, the mechanism(s) of hepatotoxicity induced by these drugs is not clearly understood yet, and no hepatoprotective agent has been developed against this complication. METHODS The protective effect of N-acetylcysteine (NAC) against statins-induced cytotoxicity was evaluated by using freshly isolated rat hepatocytes. Hepatocytes were prepared by the method of collagenase enzyme perfusion via portal vein. This technique is based on liver perfusion with collagenase after removal of calcium ion (Ca2+) with a chelator (ethylene glycol tetra acetic acid (EGTA) 0.5 mM). The level of parameters such as cell death, ROS formation, lipid peroxidation, mitochondrial membrane potential (MMP) in the statins-treated hepatocytes were determined. Additionally, the mentioned markers were assessed in the presence of NAC. RESULTS Incubation of hepatocytes with the statins resulted in cytotoxicity characterized by an elevation in cell death, increasing ROS generation and consequently lipid peroxidation and impairment of mitochondrial function. Administration of NAC caused reduction in amount of ROS formation, lipid peroxidation and finally, cell viability and mitochondrial membrane potential (MMP) were improved. CONCLUSION This study confirms that oxidative stress and consequently mitochondrial dysfunction is one of the mechanisms underlying the statins-induced liver injury and treating hepatocytes by NAC (200 μM) attenuates this cytotoxicity.

Efficiency of hepatocyte pretreatment with coenzyme Q10 against statin toxicity

Summary Statins are potent cholesterol-lowering drugs that can have serious adverse effects on the muscles and liver. The aim of our in vitro study was to establish the protective effect of coenzyme Q10 (CoQ10, in its optimal dose of 200 μmol L-1) against cytotoxicity induced by atorvastatin, simvastatin, and lovastatin in isolated rat hepatocytes by observing parameters such as cell death, reactive oxygen species formation, lipid peroxidation, mitochondrial membrane potential, and cellular reduced and oxidised glutathione content. Our findings have shown that pretreatment with CoQ10 was effective in reducing the toxic effects of statins in rat hepatocytes. This work demonstrates that the addition of CoQ10 to statin treatment regimens may protect hepatocytes (and also other types of cells) from statin-induced injuries and alleviate their side effects. Sažetak Statini su snažni lijekovi za snižavanje kolesterola, koji mogu izazvati ozbiljne nuspojave u mišićima i jetrima. Svrha je ovog in vitro istraživanja bila utvrditi zaštitno djelovanje koenzima Q10 (CoQ10, u optimalnoj dozi od 200 μmol L-1) protiv citotoksičnosti atorvastatina, simvastatina i lovastatina u izoliranih štakorskih hepatocita kroz parametre poput vijabilnosti, nastanka reaktivnih kisikovih čestica, lipidne peroksidacije, potencijala mitohondrijske membrane te reduciranog i oksidiranog glutationa. Rezultati su pokazali da predtretman štakorskih hepatocita CoQ10 djelotvorno ublažava toksične učinke statina te da bi njegovo kombiniranje sa statinima moglo zaštititi hepatocite (i druge vrste stanica) od oštećenja izazvanih statinima te ublažiti nuspojave povezane s ovim lijekovima.

Mitochondria protection as a mechanism underlying the hepatoprotective effects of glycine in cholestatic mice

Cholestasis is the stoppage of bile flow which could lead to serious clinical complications if not managed. Cytotoxic bile acids are involved in the pathogenesis of liver injury during cholestasis. There are no promising pharmacological interventions against cholestasis and its associated complications. This study examined the impact of glycine supplementation on liver mitochondria as a major target of bile acids-induced toxicity during cholestasis. Mice underwent BDL operation and received glycine (0.25% and 1% w:v in drinking water). Blood and liver samples were collected at scheduled time intervals (3, 7, and 14 days after BDL surgery). Plasma biomarkers of liver injury, along with markers of oxidative stress in the liver tissue were evaluated. Furthermore, liver mitochondria were isolated, and several mitochondrial indices were assessed. BDL-induced cholestasis was evident in mice as a significant elevation in plasma biomarkers of liver injury. Markers of oxidative stress were significantly increased in the liver of BDL animals. Liver injury was histopathologically evident by tissue necrosis, bile duct proliferation, hydropic changes, inflammation, and fibrosis. Furthermore, high level of reactive oxygen species, lipid peroxidation, depleted glutathione reservoirs, and impaired tissue antioxidant capacity were also detected in the liver of cholestatic mice. An assessment of liver mitochondrial function in BDL animals revealed an inhibition of mitochondrial dehydrogenases activity, collapse of mitochondrial membrane potential, mitochondrial swelling, and increase of reactive oxygen species (ROS), and lipid peroxidation (LPO). Furthermore, a significant decrease in mitochondrial ATP was detected in the liver mitochondria isolated from cholestatic animals. Glycine supplementation (0.25% and 1%) decreased mitochondrial swelling, ROS, and LPO. Moreover, glycine treatment improved mitochondrial membrane potential and restored liver mitochondrial ATP. On the other hand, it was found that glycine supplementation attenuated oxidative stress markers in the liver of BDL animals. Moreover, liver histopathological changes and collagen deposition were markedly mitigated by glycine treatment. The mechanisms for the beneficial effects of glycine administration in cholestatic animals might be linked to its ability for preserving cellular redox environment, preventing oxidative stress, and maintaining mitochondrial functionality.

Sulfasalazine induces mitochondrial dysfunction and renal injury

Abstract Sulfasalazine is a commonly used drug for the treatment of rheumatoid arthritis and inflammatory bowel disease. There are several cases of renal injury encompass sulfasalazine administration in humans. The mechanism of sulfasalazine adverse effects toward kidneys is obscure. Oxidative stress and its consequences seem to play a role in the sulfasalazine-induced renal injury. The current investigation was designed to investigate the effect of sulfasalazine on kidney mitochondria. Rats received sulfasalazine (400 and 600 mg/kg/day, oral) for 14 consecutive days. Afterward, kidney mitochondria were isolated and assessed. Sulfasalazine-induced renal injury was biochemically evident by the increase in serum blood urea nitrogen (BUN), gamma-glutamyl transferase (γ-GT), and creatinine (Cr). Histopathological presentations of the kidney in sulfasalazine-treated animals revealed by interstitial inflammation, tubular atrophy, and tissue necrosis. Markers of oxidative stress including an increase in reactive oxygen species (ROS) and lipid peroxidation (LPO), a defect in tissue antioxidant capacity, and glutathione (GSH) depletion were also detected in the kidney of sulfasalazine-treated groups. Decreased mitochondrial succinate dehydrogenase activity (SDA), mitochondrial depolarization, mitochondrial GSH depletion, increase in mitochondrial ROS, LPO, and mitochondrial swelling were also evident in sulfasalazine-treated groups. Current data suggested that oxidative stress and mitochondrial injury might be involved in the mechanism of sulfasalazine-induced renal injury.