Superoxide anion mediated mitochondrial dysfunction leads to hepatocyte apoptosis preferentially in the periportal region during copper toxicity in rats.
Chronic exposure to copper induces hepatocellular apoptosis with greater injury in the periportal region compared to the perivenous region. Here we have identified the factors responsible for the development of regional damage in the liver under in vivo conditions. Enhanced production of reactive oxygen species (ROS) with predominance of superoxide radical (O(2)(-)) indicates the contribution of redox imbalance in the process. This may be linked with copper catalyzed oxidation of GSH to GSSG resulting in the generation of O(2)(-). Downregulation of Cu-Zn SOD in consequence of the degradation of this enzyme, causes decreased dismutation of O(2)(-), that further contributes to the enhanced level of O(2)(-) in the periportal region. Decreased functioning of Mn SOD activity, reduction in mitochondrial thiol/disulphide ratio and generation of O(2)(-) were much higher in the mitochondria from periportal region, which point to the involvement of this organelle in the regional hepatotoxicity observed during copper exposure. This was supported by copper-mediated enhanced mitochondrial dysfunction as evident from ATP depletion, collapse of mitochondrial membrane potential (MMP) and induction of mitochondrial permeability transition (MPT). Results suggest the active participation of O(2)(-) in inducing mitochondrial dysfunction preferentially in the periportal region that eventually leads to the development of hepatotoxicity due to copper exposure under in vivo condition.
Roy
Dijendra Nath
DN
Indian Institute of Chemical Biology, CSIR, Kolkata 700032, India.
Mandal
Samir
S
Sen
Gargi
G
Biswas
Tuli
T
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002466:Cell Nucleolus / Q000187:drug effects / Q000473:pathology; D003300:Copper / Q000032:analysis / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*
D013481:Superoxides; D003300:Copper; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D005978:Glutathione