Narges Abdoli1, Yadollah Azarmi2, Mohammad Ali Eghbal2. 1. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, School of pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran. ; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. 2. Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. ; Pharmacology and Toxicology Department, School of pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran.
Abstract
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.
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.
Authors: Raúl González; Gustavo Ferrín; Ana B Hidalgo; Isidora Ranchal; Pedro López-Cillero; Mónica Santos-Gónzalez; Guillermo López-Lluch; Javier Briceño; Miguel A Gómez; Antonio Poyato; José M Villalba; Plácido Navas; Manuel de la Mata; Jordi Muntané Journal: Chem Biol Interact Date: 2009-06-11 Impact factor: 5.192