Lysosomal membrane permeabilization mediated apoptosis involve in perphenazine-induced hepatotoxicity in vitro and in vivo. (15th August 2022)

• Record Type: Journal Article
• Authors: Tao, Lei; Qing, Yingjie; Cui, Yingyue; Shi, Da; Liu, Wenting; Chen, Lei; Cao, Yu; Dai, Zhen; Ge, Xiaoming; Zhang, Ling
• Is Part Of: Toxicology letters. Volume 367(2022)
• Page Start: 76
• Page End: 87
• Publication Date: 2022-08-15
• Subjects: BCA bicinchoninic acid -- LAMP1 lysosome-associated membrane protein-1 -- DMSO dimethylsulfoxide -- FBS fetal bovine serum -- LMP lysosomal membrane permeabilization -- MTT 3-(4, 5-dimethylthiazol-2-yl)−2, 5-diphenyltetrazolium bromide -- PARP poly (ADP-ribose) polymerase -- PBS phosphate-buffered saline -- PVDF polyvinylidene difluoride -- ECL enhanced chemiluminescence -- CTSB cathepsin B -- CTSD cathepsin D; Perphenazine -- Liver injury -- Apoptosis -- LMP -- Lysosome; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2022.07.814
• Languages: English
• ISSNs: 0378-4274

Abstract

Abstract: Antipsychotic drugs represent a class of lysosomotropic drugs widely used in clinical practice. However, the hepatotoxicity of these drugs has been reported in recent years. Therefore, understanding the changes in cellular homeostasis mediated by these drugs is of great significance for revealing the true mechanisms underlying hepatotoxicity. Perphenazine is a classical antipsychotic drug that can reportedly induce extrapyramidal and sympatholytic side effects. The present research focuses on the toxicity effect of perphenazine on normal human hepatocytes. To assess the hepatotoxicity of continuous administration of perphenazine and investigate potential mechanisms related to apoptosis, human normal L02 hepatocytes were exposed to 10–40 μM perphenazine in vitro. The results showed that perphenazine inhibited cell viability in a concentration and time-dependent manner. Furthermore, 30 μM perphenazine induced intense lysosome vacuolation, impaired lysosomal membrane, and induced lysosomal membrane permeabilization (LMP), ultimately triggering lysosomal cell death in L02 cells. Knockdown cathepsin D( CTSD) also ameliorated perphenazine-induced liver injury via the inhibition of LMP. In vivo, ICR mice received intragastric administration of 10–180 mg/kg B.W. perphenazine every other day for 21 days. 180 mg/kg perphenazine significantly increased histological injury and aminotransferases compared with control. Taken together, our findings suggest that perphenazine can trigger hepatotoxicity through lysosome disruption both in vitro and in vivo. Highlights: Perphenazine induced lysosomal membrane permeability and apoptosis in L02 cells. The accumulation of perphenazine in the lysosomes may be an important cause of hepatotoxicity. Knockdown of CTSD also ameliorates perphenazine-induced hepatocytes injury by inhibiting LMP. Perphenazine at certain doses significantly increased liver tissue damage and transaminases in vivo.