Repository of Research and Investigative Information

Repository of Research and Investigative Information

دانشگاه علوم پزشکی و خدمات بهداشتی درمانی زنجان

A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis

(2012) A new approach on valproic acid induced hepatotoxicity: Involvement of lysosomal membrane leakiness and cellular proteolysis. Toxicology in Vitro. pp. 545-551.

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Although valproic acid (VPA) a proven anticonvulsant agent thought to have relatively few side-effects VPA has been referred as the third most common xenobiotic suspected of causing death due to liver injury. In this study the cellular pathways involved in VPA hepatotoxicity were investigated in isolated rat hepatocytes. Accelerated cytotoxicity mechanism screening (ACMS) techniques using fluorescent probes including, ortho-phthalaldehyde, rhodamine 123 and acridine orange were applied for measurement of ROS formation, glutathione depletion, mitochondrial membrane potential and lysosomal membrane damage, respectively. Our results showed that cytotoxic action of VPA is mediated by lysosomal membrane leakiness along with reactive oxygen species (ROS) formation and decline of mitochondrial membrane potential before cell lysis ensued. Incubation of hepatocytes with VPA also caused rapid hepatocyte glutathione (GSH) depletion which is another marker of cellular oxidative stress. Most of the VPA induced GSH depletion could be attributed to the expulsion of GSSG. Our results also showed that CYP2EI is involved in the mechanism of VPA cytotoxicity. We finally concluded that VPA hepatotoxicity is a result of metabolic activation by CYP2E1 and ROS formation, leading to lysosomal labialization, mitochondrial/lysosomal toxic cross-talk and finally general cellular proteolysis in the rat hepatocytes. (C) 2012 Elsevier Ltd. All rights reserved.

Item Type: Article
Keywords: Author Keywords:Valproic acid; Cellular proteolysis; Lysosomes; Oxidative stress; Mitochondrial/lysosomal cross-talk; Rat hepatocytes KeyWords Plus:HEPATOCYTE CYTOTOXIC MECHANISMS; CULTURED RAT HEPATOCYTES; FATTY LIVER-DISEASE; TOXIC CROSS-TALK; OXIDATIVE STRESS; SODIUM VALPROATE; THERAPY; METABOLITES; PROTECTION; CARNITINE
Page Range: pp. 545-551
Journal or Publication Title: Toxicology in Vitro
Abstract and Indexing: ISI, Pubmed, Scopus
Quartile : Q2
Volume: 26
Number: 4
Publisher: scopus
Depositing User: خانم مریم زرقانی

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