Lysosomal Oxidative Stress Cytotoxicity Induced By Para-phenylenediamine Redox Cycling In Hepatocytes

How to Cite:Jalal PourahmadFarzad KobarfardAtaollah ShakooriLysosomal Oxidative Stress Cytotoxicity Induced By Para-phenylenediamine Redox Cycling In Hepatocytes.Iran J Pharm Res.3(4):e128207.https://doi.org/10.22037/ijpr.2010.601.

Abstract

It has already been reported that muscle necrosis induced by various phenylenediamine derivatives are correlated with their autoxidation rate. Now in a more detailed investigation of the cytotoxic mechanism using a model system of isolated hepatocytes and ring-methylated structural isomer durenediamine (DD) we have shown that under aerobic conditions, phenylenediamine induced cytotoxicity and ROS formation were markedly increased by inactivating DT-diaphorase but were prevented by a subtoxic concentration of the mitochondrial respiratory inhibitor cyanide. This suggests that the H₂O₂ generation could be attributed to a futile two electron redox cycle involving oxidation of phenylenediamine to the corresponding diimine by the mitochondrial electron transfer chain and re-reduction by the DT- diaphorase. The subcellular organelle oxidative stress effects leading to cytotoxicity has not yet been identified. Hepatocyte mitochondrial membrane potential was only slightly decreased by phenylenediamine before cytotoxicity ensued. However phenylenediamine induced lysosomal damage and hepatocyte protease activation. Endocytosis inhibitors, lysosomotropic agents or lysosomal protease inhibitors also prevented phenylenediamine induced cytotoxicity.

Furthermore desferoxamine (a ferric chelator), antioxidants or ROS scavengers (catalase, mannitol, tempol or dimethylsulfoxide) prevented phenylenediamine cytotoxicity. It is concluded that H₂O₂ reacts with lysosomal Fe²⁺ to form “ROS” which causes lysosomal lipid peroxidation, membrane disruption, protease release and cell death.

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Author(s):

Jalal Pourahmad:[PubMed][Scholar]
Farzad Kobarfard:[PubMed][Scholar]
Ataollah Shakoori:[PubMed][Scholar]