Title: Dioxin increases reactive oxygen production in mouse liver mitochondria.
Authors: Senft, Albert P; Dalton, Timothy P; Nebert, Daniel W; Genter, Mary Beth; Hutchinson, Richard J; Shertzer, Howard G
Published In Toxicol Appl Pharmacol, (2002 Jan 1)
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.
PubMed ID: 11781075
MeSH Terms: Aconitate Hydratase/metabolism; Adenosine Triphosphate/metabolism; Animals; Dioxins/pharmacology*; Energy Metabolism/drug effects; Female; Glutathione Peroxidase/metabolism; Glutathione Reductase/metabolism; Glutathione/metabolism; Hydrogen Peroxide/metabolism; Indicators and Reagents; Luminol/diagnostic use; Mice; Mice, Inbred C57BL; Mitochondria, Liver/drug effects; Mitochondria, Liver/enzymology; Mitochondria, Liver/metabolism*; Oxidation-Reduction; Oxidative Stress/drug effects; Proteins/metabolism; Reactive Oxygen Species/metabolism*; Research Support, U.S. Gov't, P.H.S.; Superoxide Dismutase/metabolism