> Persistent activation of the AhR is probably responsible for toxic
> responses in experimental animals and humans.
Dioxin increases reactive oxygen production in mouse liver
mitochondria.
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 re****t to
show that dioxin increases mitochondrial respiration-dependent
reactive oxygen production, which may play an im****tant role in dioxin-
induced toxicity and disease. PMID: 11781075
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