Involvement of Four Different Intracellular Sites in Chloroacetaldehyde- Induced Oxidative Stress Cytotoxicity

نویسندگان

  • Faezeh Rahmani Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran.
  • Jalal Pourahmad Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran.
  • Mir-Jamal Hosseini Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran. Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
  • Mohammad Reza Eskandari Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
چکیده مقاله:

Chloroacetaldehyde (CAA) is a chlorination by-product in finished drinking water and a toxic metabolite of a wide variety of industrial chemicals (e.g. vinyl chloride) and chemotherapeutic agents (e.g. cyclophosphamide and ifosfamide). In this research, the cytotoxic mechanisms of CAA in freshly isolated rat hepatocytes were investigated.CAA cytotoxicity was associated with reactive oxygen species (ROS) formation and glutathione depletion suggesting that oxidative stress contributed to the CAA cytotoxic mechanism. CAA-induced oxidative stress cytotoxicity markers were significantly prevented by antioxidants, ROS scavengers, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors, ATP generators and xanthine oxidase inhibitor. In our study the hepatocyte mitochondrial membrane potential was rapidly decreased by CAA which was prevented by antioxidants and ROS scavenger indicating that mitochondrial membrane damage was a consequence of ROS formation. CAA cytotoxicity was also associated with lysosomal membrane rupture. Our findings showed that at least four different intracellular sources including: metabolic enzymes cytochrome P450 and xanthine oxidase, mitochondrial respiratory chain disruption and lysosomal Haber-weiss reaction, were involved in CAA induced ROS formation and other subsequent cytotoxic events. Our other interesting finding was that the lysosomotropic agents prevented CAA induced mitochondrial membrane potential collapse and mitochondrial MPT pore sealing agents inhibited lysosomal membrane damage caused by CAA. It can therefore be suggested that there is probably a toxic interaction (cross-talk) between mitochondrial and lysosomal oxidative stress generating systems, which potentiates each organelle damage and ROS formation in CAA- induced hepatotoxicity.

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involvement of four different intracellular sites in chloroacetaldehyde- induced oxidative stress cytotoxicity

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عنوان ژورنال

دوره 11  شماره 1

صفحات  265- 276

تاریخ انتشار 2012-03-11

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