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.

Histological Study of the Effects of Olanzapine on the Liver of Adult Male Albino Rat with and without Vitamin C

“…Also decreased lipid peroxidation and glutathione depletion occurred. The end result of these changes was cell lysis [36] .…”

Oxidative Stress and Schizophrenia

“…Al-Chalabi, et al [6] showed that olanzapine could improve plasma total antioxidant status (TAS) and alleviate lipid peroxidation damage. Eftekhari, et al [15] found, in animal experiments, that olanzapine induced oxidative stress and hepatocytotoxicity and associated with the CYP450 enzyme. Olanzapine and clozapine were recently thought to be more effective than risperidone, quetiapine, ziprasidone and haloperidol in resisting oxidation [16] .…”

Venlafaxine-Induced Cytotoxicity Towards Isolated Rat Hepatocytes Involves Oxidative Stress and Mitochondrial/Lysosomal Dysfunction

“…The utilized doses for ROS scavengers (butylated hydroxytoluen (BHT) and α-tocopherol succinate), MPT pore sealing agents (trifluoperazine and carnitine), ATP generators (l-glutamine and fructose), lysosomotropic agents (methylamine and chloroquine) and CYP450 inhibitors (cimetidine and 4-methylpyrazole) were chosen from similar experiments that were done on rat hepatocytes. [24][25][26] We also investigated the aforementioned doses in our isolation system and perceived that they have maximal protective impacts on the cytotoxicity indicators (data not shown).…”