title: The effect of idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria.
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.
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Denver, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Shivaram
authors.forename: B M
authors.initials: BM
authors.lastname: Winklhofer-Roob
authors.forename: M S
authors.initials: MS
authors.lastname: Straka
authors.forename: M W
authors.initials: MW
authors.lastname: Devereaux
authors.forename: G
authors.initials: G
authors.lastname: Everson
authors.forename: G W
authors.initials: GW
authors.lastname: Mierau
authors.forename: R J
authors.initials: RJ
authors.lastname: Sokol
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D016227:Benzoquinones / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury; D005999:Glycochenodeoxycholic Acid / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley; D019802:Succinic Acid / Q000494:pharmacology; D013655:Taurochenodeoxycholic Acid / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014451:Ubiquinone / Q000031:analogs & derivatives
chemical_list: D000975:Antioxidants; D016227:Benzoquinones; D001647:Bile Acids and Salts; D017392:Thiobarbituric Acid Reactive Substances; D014451:Ubiquinone; D013655:Taurochenodeoxycholic Acid; D005999:Glycochenodeoxycholic Acid; D019802:Succinic Acid; D007770:L-Lactate Dehydrogenase; C036619:idebenone