Involvement of Lysosomal Labilisation and Lysosomal/mitochondrial Cross-Talk in Diclofenac Induced Hepatotoxicity

Document Type : Research article

Authors

1 Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. Box 14155-6153, Tehran , Iran.

2 Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.

3 Faculty of Pharmacy, Shahid Beheshti University of Medical Sciences, P.O. Box 14155-6153, Tehran, Iran.

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 mitochondrial 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.

Keywords

Iranian Journal of Pharmaceutical Research
Volume 10, Issue 4 - Serial Number 4
Autumn 2011
Pages 877-887

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