Generation of hydroperoxides in isolated rat hepatocytes and hepatic mitochondria exposed to hydrophobic bile acids
RJ Sokol, BM Winklhofer-Roob, MW Devereaux… - Gastroenterology, 1995 - Elsevier
RJ Sokol, BM Winklhofer-Roob, MW Devereaux, JM McKim Jr
Gastroenterology, 1995•ElsevierBackground & Aims: The mechanisms causing liver injury in cholestatic diseases are
unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during
cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The
aim of this study was to determine if hydrophobic bile acid toxicity is associated with
increased hydroperoxide generation in isolated rat hepatocytes and mitochondria. Methods:
Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0–2000 μmol/L) or …
unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during
cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The
aim of this study was to determine if hydrophobic bile acid toxicity is associated with
increased hydroperoxide generation in isolated rat hepatocytes and mitochondria. Methods:
Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0–2000 μmol/L) or …
Background & Aims
The mechanisms causing liver injury in cholestatic diseases are unclear. The hypothesis that accumulation of hydrophobic bile acids in hepatocytes during cholestasis leads to generation of oxygen free radicals and oxidative injury was tested. The aim of this study was to determine if hydrophobic bile acid toxicity is associated with increased hydroperoxide generation in isolated rat hepatocytes and mitochondria.
Methods
Hepatocytes were exposed to taurochenodeoxycholic acid (TCDC; 0–2000 μmol/L) or taurocholic acid (TC; 1000 μmol/L), and cellular injury, intracellular hydroperoxide generation, and thiobarbituric acid-reacting substances (TBARS) were measured. Isolated mitochondria were incubated with 400 μmol/L chenodeoxycholic acid or 400 μmol/L cholic acid, and hydroperoxide generation was measured fluorometrically.
Results
Hepatocyte injury, hydroperoxide generation, and TBARS increased over 4 hours on exposure to TCDC but not TC. Hydroperoxide generation preceded hepatocyte injury and accumulation of TBARS. Preincubation of hepatocytes with the antioxidant, d-α-tocopheryl succinate, completely abrogated cellular injury, hydroperoxide, and TBARS generation. Hydroperoxide generation was increased in mitochondria exposed to chenodeoxycholic acid.
Conclusions
Intracellular generation of hydroperoxides by mitochondria appears to be an early event in hydrophobic bile acid-induced hepatocyte toxicity. Antioxidants may be of benefit in cholestasis.
Elsevier
