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1.
Free Radic Biol Med ; 33(9): 1268-78, 2002 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-12398935

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin; TCDD) is a pervasive environmental contaminant that induces hepatic and extrahepatic oxidative stress. We have previously shown that dioxin increases mitochondrial respiration-dependent reactive oxygen production. In the present study we examined the dependence of mitochondrial reactive oxygen production on the aromatic hydrocarbon receptor (AHR), cytochrome P450 1A1 (CYP1A1), and cytochrome P450 1A2 (CYP1A2), proteins believed to be important in dioxin-induced liver toxicity. Congenic Ahr(-/-), Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, and C57BL/6J inbred mice as their Ahr/Cyp1a1/Cyp1a2(+/+) wild-type (wt) counterparts, were injected intraperitoneally with dioxin (15 microg/kg body weight) or corn-oil vehicle on 3 consecutive days. Liver mitochondria were examined 1 week following the first treatment. The level of mitochondrial H(2)O(2) production in vehicle-treated Ahr(-/-) mice was one fifth that found in vehicle-treated wt mice. Whereas dioxin caused a rise in succinate-stimulated mitochondrial H(2)O(2) production in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, this increase did not occur with the Ahr(-/-) knockout. The lack of H(2)O(2) production in Ahr(-/-) mice was not due to low levels of Mn(2+)-superoxide dismutase (SOD2) as shown by Western immunoblot analysis, nor was it due to high levels of mitochondrial glutathione peroxidase (GPX1) activity. Dioxin decreased mitochondrial aconitase (an enzyme inactivated by superoxide) by 44% in wt mice, by 26% in Cyp1a2(-/-) mice, and by 24% in Cyp1a1(-/-) mice; no change was observed in Ahr(-/-) mice. Dioxin treatment increased mitochondrial glutathione levels in the wt, Cyp1a1(-/-), and Cyp1a2(-/-) mice, but not in Ahr(-/-) mice. These results suggest that both constitutive and dioxin-induced mitochondrial reactive oxygen production is associated with a function of the AHR, and these effects are independent of either CYP1A1 or CYP1A2.


Assuntos
Mitocôndrias Hepáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores de Hidrocarboneto Arílico/metabolismo , Aconitato Hidratase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Western Blotting , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo , Dibenzodioxinas Policloradas/toxicidade , Ácido Succínico/metabolismo , Superóxido Dismutase/metabolismo
2.
Toxicol Appl Pharmacol ; 178(1): 15-21, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11781075

RESUMO

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.


Assuntos
Dioxinas/farmacologia , Mitocôndrias Hepáticas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Aconitato Hidratase/metabolismo , Trifosfato de Adenosina/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Redutase/metabolismo , Peróxido de Hidrogênio/metabolismo , Indicadores e Reagentes , Luminol , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Hepáticas/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Oxirredução , Estresse Oxidativo/efeitos dos fármacos , Proteínas/metabolismo , Superóxido Dismutase/metabolismo
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