The effect of
idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to
isolated rat hepatocytes and hepatic mitochondria.
Shivaram KN, Winklhofer-Roob BM, Straka MS,
Devereaux MW, Everson G, Mierau GW,
Sokol RJ.
Department of Pediatrics,
University of Colorado School of Medicine,
Denver, CO USA
Abstract
Oxidant stress induced by
hydrophobic bile acids has been implicated in the pathogenesis of liver injury
in cholestatic liver disorders. We evaluated the effect of idebenone, a
coenzyme Q analogue, on taurochenodeoxycholic acid (TCDC)-induced cell injury
and oxidant stress in isolated rat hepatocytes and on glycochenodeoxycholic
acid (GCDC)-induced generation of hydroperoxides in fresh hepatic
mitochondria. Isolated rat hepatocytes in suspension under 9% oxygen
atmosphere were preincubated with 0, 50, and 100 micromol/l idebenone for 30
min and then exposed to 1000 micromol/l TCDC for 4 h. LDH release (cell
injury) and thiobarbituric acid reactive substances (measure of lipid
peroxidation) increased after TCDC exposure but were markedly suppressed by
idebenone pretreatment. In a second set of experiments, the addition of 100
micromol/l idebenone up to 3 h after hepatocytes were exposed to 1000 micromol/l
TCDC resulted in abrogation of subsequent cell injury and markedly reduced
oxidant damage to hepatocytes. Chenodeoxycholic acid concentrations increased
to 5.15 nmol/10(6) cells after 2 h and to 7.05 after 4 h of incubation of
hepatocytes with 1000 micromol/l TCDC, and did not differ in the presence of
idebenone. In freshly isolated rat hepatic mitochondria, when respiration was
stimulated by succinate, 10 micromol/l idebenone abrogated the generation of
hydroperoxides during a 90-minute exposure to 400 micromol/l GCDC. These data
demonstrate that idebenone functions as a potent protective hepatocyte
antioxidant during hydrophobic bile acid toxicity, perhaps by reducing
generation of oxygen free radicals in mitochondria.
