title: Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes.
abstract: 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.
authors.affiliation: Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Narges
authors.initials: N
authors.lastname: Abdoli
authors.forename: Reza
authors.initials: R
authors.lastname: Heidari
authors.forename: Yadollah
authors.initials: Y
authors.lastname: Azarmi
authors.forename: Mohammad Ali
authors.initials: MA
authors.lastname: Eghbal
mesh_terms: D000818:Animals; D000069059:Atorvastatin; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005978:Glutathione / Q000378:metabolism; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D006538:Heptanoic Acids / Q000633:toxicity; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D015227:Lipid Peroxidation / Q000187:drug effects; D008148:Lovastatin / Q000633:toxicity; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D011758:Pyrroles / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000633:toxicity
chemical_list: D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D017382:Reactive Oxygen Species; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin; D005978:Glutathione; D019803:Glutathione Disulfide