Mechanistic approach for thioridazine-induced hepatotoxicity and potential benefits of melatonin and/or coenzyme Q10 on freshly isolated rat hepatocytes

Abstract

Thioridazine (TZ) is used mainly in the treatment of schizophrenia. However, hepatotoxicity as a life-threatening adverse effect is associated with its clinical use. In this context, we examined the cytotoxic mechanisms of TZ on freshly isolated rat hepatocytes to better understanding of the pathogenesis of TZ-induced hepatotoxicity. Hepatocytes were prepared by the method of collagenase enzyme perfusion via the portal vein. The level of parameters such as cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), mitochondrial membrane potential (MMP), lysosomal membrane integrity and cellular glutathione (GSH) content in TZ-treated and non-treated hepatocytes were determined and the mentioned markers were assessed in the presence of Coenzyme Q10 and/or melatonin. Results showed that TZ caused an increase in ROS formation as well as induction of LPO and GSH depletion. Moreover, mitochondria and lysosomes seem to be targets of TZ-induced toxicity. The administration of Coenzyme Q10 and/or melatonin efficiently decreased the rate of ROS formation, LPO and improved cell viability, MMP, GSH level and lysosome membrane integrity. This study proposes the possible protective role of Coenzyme Q10 and/or melatonin against TZ-induced cellular injury probably through their radical scavenging properties and their effects on mitochondria and lysosomes.