title: Dioxin increases reactive oxygen production in mouse liver mitochondria.
abstract: Dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin; TCDD) causes an oxidative stress response in liver and several extrahepatic tissues. The subcellular sources and underlying mechanisms of dioxin-induced reactive oxygen, however, are not well understood. In this study, we examined whether mitochondria, organelles that consume the majority of cellular oxygen, might be a source of dioxin-induced reactive oxygen. Female C57BL/6 mice were treated with dioxin (15 microg/kg body wt ip) on 3 consecutive days, and liver mitochondria were examined at 1, 4, and 8 weeks after the first treatment. Mitochondrial aconitase activity, an enzyme inactivated by superoxide, was decreased by 44% at 1 week, 22% at 4 weeks, and returned to control levels at 8 weeks. Dioxin elevated succinate-stimulated mitochondrial H2O2 production twofold at 1 and 4 weeks; H2O2 production remained significantly elevated at 8 weeks. The enhanced H2O2 production was due to neither increased Mn-superoxide dismutase activity nor decreased mitochondrial glutathione peroxidase activity. Dioxin treatment augmented mitochondrial glutathione, but not glutathione disulfide levels, a result that might be explained by increased mitochondrial glutathione reductase activity. Liver ATP levels were significantly lowered at 1 and 4 weeks, the peak times of mitochondrial reactive oxygen production. Increased dioxin-stimulated reactive oxygen at 1 and 4 weeks did not appear to be related to the observed decrease in cytochrome oxidase activity, since State 3 and State 4 respiration were not diminished. To our knowledge, this is the first report to show that dioxin increases mitochondrial respiration-dependent reactive oxygen production, which may play an important role in dioxin-induced toxicity and disease.
authors.affiliation: Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, Ohio 45267-0056, USA.
authors.forename: Albert P
authors.initials: AP
authors.lastname: Senft
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Dalton
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Nebert
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Genter
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Hutchinson
authors.forename: Howard G
authors.initials: HG
authors.lastname: Shertzer
mesh_terms: D000154:Aconitate Hydratase / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004147:Dioxins / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D007202:Indicators and Reagents; D008165:Luminol; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011506:Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D004147:Dioxins; D007202:Indicators and Reagents; D011506:Proteins; D017382:Reactive Oxygen Species; D008165:Luminol; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D005979:Glutathione Peroxidase; D013482:Superoxide Dismutase; D005980:Glutathione Reductase; D000154:Aconitate Hydratase; D005978:Glutathione