Dioxin Causes a Sustained Oxidative Stress Response in the Mouse

Shertzer, Howard G.; Nebert, Daniel W.; Puga, Alvaro; Ary, Michelle; Sonntag, David M; Dixon, Kathleen; Robinson, Lindsey J.; Cianciolo, Eli; Dalton, Timothy P.

doi:10.1006/bbrc.1998.9753

Cited by 145 publications

(87 citation statements)

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“…TCB also stimulated ROS production in microsomes from insect cells expressing human CYP1A1, but not in microsomes from cells expressing human CYP1A2 (Schlezinger et al, 1999). These results may explain the previous observation in mice that TCDD produced a sustained elevation of hepatic CYP1A2 activity, while CYP1A1 showed a transient increase, followed by a rapid loss (Shertzer et al, 1998).…”

Section: Role Of Cytochrome P450 Enzymes In Tcdd Toxicitymentioning

confidence: 48%

“…The incomplete reduction of O 2 by several enzyme systems, in particular the cytochrome P450 enzymes that are induced by TCDD, is known to result in the generation of superoxide and hydrogen peroxide through poor coupling of electron flow. TCDD has been implicated in the formation of the superoxide anion in rat brain (Hassoun et al, 2003) and hydrogen peroxide in mouse liver (Shertzer et al, 1998;Senft et al, 2002a), with resultant generation of lipid peroxides in rat brain, mouse liver and rat testis (Shertzer et al, 1998;Hassoun et al, 2003;Latchoumycandane et al, 2003). Several lines of evidence support the AHR as a mediator of oxidative stress.…”

Section: Tcdd-mediated Perturbation Of Redox Homeostasismentioning

confidence: 99%

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Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

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ᮀTCDD and other polyhalogenated aromatic hydrocarbon ligands of the aryl hydrocarbon receptor (AHR) have been classically considered as non-genotoxic compounds because they fail to be directly mutagenic in either bacteria or most in vitro assay systems. They do so in spite of having repeatedly been linked to oxidative stress and to mutagenic and carcinogenic outcomes. Oxidative stress, on the other hand, has been used as a marker for the toxicity of dioxin and its congeners. We have focused this review on the connection between oxidative stress induction and the toxic effects of fetal and adult dioxin exposure, with emphasis on the large species difference in sensitivity to this agent. We examine the roles that the dioxin-inducible cytochromes P450s play in the cellular and toxicological consequences of dioxin exposure with emphasis on oxidative stress involvement. Many components of the health consequences resulting from dioxin exposure may be attributable to epigenetic mechanisms arising from prolonged reactive oxygen generation.

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Section: Role Of Cytochrome P450 Enzymes In Tcdd Toxicitymentioning

confidence: 48%

Section: Tcdd-mediated Perturbation Of Redox Homeostasismentioning

confidence: 99%

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

et al. 2005

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“…Unlike acute exposures, however, long-term exposures to PHAH may change the capacity of DNA repair by modifying the expression of proteins involved in DNA repair, analogous to how PHAH changes the expression of metabolic enzymes [38][39][40]. Additionally, it has been proposed that DNA repair proteins can be impaired by mutations caused by the slow accumulation of DNA adducts over a long period of time [37].…”

Section: Resultsmentioning

confidence: 99%

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Jeong

Walker

Burgin

et al. 2008

Free Radical Biology and Medicine

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Oxidative DNA damage is one of the key events thought to be involved in mutation and cancer. The present study examined the accumulation of M 1 dG, 3-(2′-deoxy-β-D-erythro-pentofuranosyl)-pyrimido[1,2-a]-purin-10(3H)-one, DNA adducts after single dose or one-year exposure to polyhalogenated aromatic hydrocarbons (PHAH) in order to evaluate the potential role of oxidative DNA damage in PHAH toxicity and carcinogenicity. The effect of PHAH exposure on the number of M 1 dG adducts was explored initially in female mice exposed to a single dose of either 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or a PHAH mixture. This study demonstrated that a single exposure to PHAH had no significant effect on the number of M 1 dG adducts compared to the corn oil control group. The role of M 1 dG adducts in polychlorinated biphenyl (PCB) induced toxicity and carcinogenicity was further investigated in rats exposed for a year to PCB 153, PCB 126, or a mixture of the two. PCB 153, at doses up to 3000 μg/kg/d, had no significant effect on the number of M 1 dG adducts in liver and brain tissues from the exposed rats compared to controls. However, 1000 ng/kg/ d of PCB 126 resulted in M 1 dG adduct accumulation in the liver. More importantly, co-administration of equal proportions of PCB 153 and PCB 126 resulted in dose-dependent increases in M 1 dG adduct accumulation in the liver from 300-1000 ng/kg/d of PCB 126 with 300-1000 μg/kg/d of PCB 153. Interestingly, the co-administration of different amounts of PCB 153 with fixed amounts of PCB 126 demonstrated more M 1 dG adduct accumulation with higher doses of PCB 153. These results are consistent with the results from cancer bioassays that demonstrated a synergistic effect between PCB 126 and PCB 153 on toxicity and tumor development. In summary, the results from the present study support the hypothesis that oxidative DNA damage plays a key role in toxicity and carcinogenicity following long-term PCB exposure.

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“…CYP1A4 is inactive in aa metabolism, but CYP1A1 has been implicated in generation of reactive oxygen intermediates which have been considered as possible mediators of some of the adverse effects of TCDD [62]. Moreover, CYP1A1 knockout mice exhibit reduced TCDD toxicity [63].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

Labitzke¹,

Diani-Moore²,

Rifkind³

2007

Archives of Biochemistry and Biophysics

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Several P450 enzymes localized in the endoplasmic reticulum and thought to be involved primarily in xenobiotic metabolism, including mouse and rat CYP1A1 and mouse CYP1A2, have also been found to translocate to mitochondria. We report here that the environmental toxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces enzymatically active CYP1A4/1A5, the avian orthologs of mammalian CYP1A1/1A2, in chick embryo liver mitochondria as well as in microsomes. P450 proteins and activity levels (CYP1A4-dependent 7-ethoxyresorufin-O-deethylase and CYP1A5-dependent arachidonic acid epoxygenation) in mitochondria were 23-40% of those in microsomes. DHET formation by mitochondria was twice that of microsomes and was attributable to a mitochondrial soluble epoxide hydrolase as confirmed by Western blotting with antiEPHX2, conversion by mitochondria of pure 11,12 and 14,15-EET to the corresponding DHETs and inhibition of DHET formation by the soluble epoxide hydrolase inhibitor, 12(-3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA). TCDD also suppressed formation of mitochondrial and microsomal 20-HETE. The findings newly identify mitochondria as a site of P450-dependent arachidonic acid metabolism and as a potential target for TCDD effects. They also demonstrate that mitochondria contain soluble epoxide hydrolase and underscore a role for CYP1A in endobiotic metabolism.

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Dioxin Causes a Sustained Oxidative Stress Response in the Mouse

Cited by 145 publications

References 2 publications

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Induction of Oxidative Stress Responses by Dioxin and other Ligands of the Aryl Hydrocarbon Receptor

Accumulation of M1dG DNA adducts after chronic exposure to PCBs, but not from acute exposure to polychlorinated aromatic hydrocarbons

Mitochondrial P450-dependent arachidonic acid metabolism by TCDD-induced hepatic CYP1A5; conversion of EETs to DHETs by mitochondrial soluble epoxide hydrolase

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