Roles of reactive oxygen species, NF-κB, and peroxiredoxins in glycochenodeoxycholic acid-induced rat hepatocytes death

The aim of this study was to determine the roles of reactive oxygen species (ROS), NF-kappaB and antioxidants in glycochenodeoxycholic acid (GCDC, 0-400 mumol/l, 0.53 h)-induced hepatocytes death. The differential uptake of ethidium bromide and acridine orange revealed that apoptotic death occurred dose-dependently in GCDC-treated hepatocytes whereas necrotic death was prominent especially at higher GCDC concentrations ( greater than or equal to 200 mumol/l). ROS generation measured fluorometrically either by a confocal laser microscope or by a microplate fluorescence reader was increased dose-dependently. The dose-dependent NF-kappaB activation with the significant IkappaB-alpha decrease preceded both hepatocyte cell death and the alteration of antioxidant enzymes. The Cu/Zn-SOD level among several antioxidants, we checked, remained unchanged. In contrast, the catalase level and its enzymatic activity were markedly decreased only at 400 mumol/l. The Prx I and Prx II, newly defined antioxidant enzymes reducing H2O2 levels were decreased at the 200 and 400 mumol/l. These observations point to ROS generation in the GCDC-treated hepatocyte as the proximate event that triggers NF-kappaB activation, IKB-alpha proteolysis, Prx depletion, and finally cell death. And oxidative stress may be more related to necrotic cell death in GCDC-treated hepatocytes. Copyright (C) 2003 S. KargerAG, Basel.