Involvement of oxidative stress and mitochondrial/lysosomal cross-talk in olanzapine cytotoxicity in freshly isolated rat hepatocytes

Abstract

1. Olanzapine (OLZ) is a widely used atypical antipsychotic agent for the treatment of schizophrenia and other disorders. Serious hepatotoxicity and elevated liver enzymes have been reported in patients receiving OLZ. However, the cellular and molecular mechanisms of the OLZ hepatotoxicity are unknown.

2. In this study, the cytotoxic effect of OLZ on freshly isolated rat hepatocytes was assessed. Our results showed that the cytotoxicity of OLZ in hepatocytes is mediated by overproduction of reactive oxygen species (ROS), mitochondrial potential collapse, lysosomal membrane leakiness, GSH depletion and lipid peroxidation preceding cell lysis. All the aforementioned OLZ-induced cellular events were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, endocytosis inhibitors and adenosine triphosphate generators. Also, the present results demonstrated that CYP450 is involved in OLZ-induced oxidative stress and cytotoxicity mechanism.

3. It is concluded that OLZ hepatotoxicity is associated with both mitochondrial/lysosomal involvement following the initiation of oxidative stress in hepatocytes.

• Hepatotoxicity
• liver damage
• mitochondrial/lysosomal dysfunction
• olanzapine
• ROS formation

Acknowledgements

The authors would like to thank Drug Applied Research Center of Tabriz University of Medical Sciences, Tabriz, Iran, for providing technical facilities. This is a report of a database from thesis entitled “Evaluation of the mechanisms of hepatic injuries induced by antipsychotic drugs” registered in “Drug Applied Research Center”. The authors are also thankful to the University’s “Students’ Research Committee” for providing technical supports to the study.

Declaration of interest

The authors declare that there are no conflicts of interest associated with this work. This research has been funded by a grant (Grant number: 101/93) from the Drug Applied Research Center of Tabriz University of Medical Sciences, Tabriz, Iran.