Repository of Research and Investigative Information

Repository of Research and Investigative Information

دانشگاه علوم پزشکی و خدمات بهداشتی درمانی زنجان

Involvement of lysosomal labilisation and lysosomal/mitochondrial cross-talk in diclofenac induced hepatotoxicity

(2011) Involvement of lysosomal labilisation and lysosomal/mitochondrial cross-talk in diclofenac induced hepatotoxicity. Iranian Journal of Pharmaceutical Research. pp. 877-887.

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Abstract

In this research, we investigated the cytotoxic mechanisms of one of the widely used pharmaceuticals that are regularly associated with the adverse effects on the liver, sometimes leading to acute liver failure, diclofenac. Diclofenac liver cytotoxicity was associated with reactive oxygen species (ROS) formation and lipid peroxidation which were inhibited by antioxidants and ROS scavengers, ferric chelator, inhibitors of reduced CYP2E1 and CYP2C9, mitochondrial permeability transition (MPT) pore sealing agents and endocytosis inhibitors. Incubation of hepatocytes with diclofenac caused rapid hepatocyte glutathione (GSH) depletion which is another marker of cellular oxidative stress. Most of the diclofenac-induced GSH depletion could be attributed to the expulsion of GSSG. Diclofenac cytotoxicity was also associated with mitochondrial injury, lysosomal membrane rupture and release of digestive proteases which were prevented by antioxidants, MPT pore sealing agents, lysosomotropic agents and inhibitors of cytochrome P450 isoenzymes. These events could cause cytochrome C release from the mitochondria] intramembrane space to cytosol. The cytochrome C release could trigger activation of caspase-3 and apoptosis. We finally concluded that diclofenac hepatotoxicity is a result of metabolic activation by CYP2E1 and CYP2C9 and ROS formation, leading to a mitochondrial/lysosomal toxic cross-talk in the liver hepatocytes.

Item Type: Article
Keywords: Author Keywords:Diclofenac; Cytochrome P450; Cytotoxicity; Mitochondria; Lysosome KeyWords Plus:MITOCHONDRIAL PERMEABILITY TRANSITION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; INDUCED OXIDATIVE STRESS; RAT HEPATOCYTES; IMMUNOCHEMICAL DETECTION; METABOLIC-ACTIVATION; PROTEIN ADDUCTS; TOXICITY; LIVER; MECHANISMS
Page Range: pp. 877-887
Journal or Publication Title: Iranian Journal of Pharmaceutical Research
Abstract and Indexing: ISI, Pubmed, Scopus
Quartile : Q4
Volume: 10
Number: 4
Publisher: scopus
Depositing User: خانم مریم زرقانی
URI: http://repository.zums.ac.ir/id/eprint/1315

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