Dioxin Increases Reactive Oxygen Production in Mouse Liver Mitochondria

• Published in: Toxicology and applied pharmacology 2002-01, Vol.178 (1), p.15-21
• Main Authors: Senft, Albert P., Dalton, Timothy P., Nebert, Daniel W., Genter, Mary Beth, Hutchinson, Richard J., Shertzer, Howard G.
• Format: Article
• Language: English
• Subjects: Aconitate Hydratase - metabolism; Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Chemical and industrial products toxicology. Toxic occupational diseases; Dioxins - pharmacology; Energy Metabolism - drug effects; Female; Glutathione - metabolism; Glutathione Peroxidase - metabolism; Glutathione Reductase - metabolism; Hydrogen Peroxide - metabolism; Indicators and Reagents; Luminol; Medical sciences; 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; Superoxide Dismutase - metabolism; Toxicology; Various organic compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1006/taap.2001.9314

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 μg/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.