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Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes
Narges Abdoli1, Reza Heidari, Yadollah Azarmi
1Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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.
Insights
Statins can harm liver cells (hepatocytes) by causing oxidative stress and damaging mitochondria. This study reveals how common statins induce liver toxicity in rats, highlighting the role of reactive oxygen species.
Area of Science:
- Biochemistry
- Toxicology
- Pharmacology
Background:
- Statins are widely prescribed lipid-lowering drugs for cardiovascular disease management.
- Hepatotoxicity is a significant adverse effect of statin therapy, but its underlying mechanisms remain unclear.
Purpose of the Study:
- To investigate the cytotoxic effects of atorvastatin, lovastatin, and simvastatin on isolated rat hepatocytes.
- To elucidate the mechanisms of statin-induced hepatotoxicity, focusing on oxidative stress and mitochondrial dysfunction.
Main Methods:
- Isolated rat hepatocytes were treated with varying doses of atorvastatin, lovastatin, and simvastatin.
- Key markers of cellular damage, including cell death, reactive oxygen species (ROS) formation, lipid peroxidation, mitochondrial membrane potential, and glutathione levels, were assessed.
Main Results:
- Statins demonstrated dose-dependent cytotoxicity in rat hepatocytes.
- Statin treatment led to increased ROS production, lipid peroxidation, and mitochondrial depolarization.
- Cellular glutathione levels decreased, with a concurrent increase in oxidized glutathione.
Conclusions:
- Statin-induced hepatotoxicity in rats is mediated by oxidative stress.
- Mitochondrial dysfunction plays a critical role in the toxicity pathway of statins toward hepatocytes.
