> Persistent activation of the AhR is probably responsible for toxic
> responses in experimental animals and humans. They are markedly tissue
> and species specific. In rodents a wasting syndrome,
> immunosuppression, teratogenicity, chloracne, and carcinogenicity/
> tumor promotion have been well studied. There is good evidence for an
> involvement for the AhR in these responses.
Glutathione redox state regulates mitochondrial reactive oxygen
production.
Oxidative stress induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD;
dioxin) is poorly understood. Following one dose of TCDD (5 microg/kg
body weight), mitochondrial succinate-dependent production of
superoxide and H2O2 in mouse liver doubled at 7-28 days, then subsided
by day 56; concomitantly, levels of GSH and GSSG increased in both
cytosol and mitochondria. Cytosol displayed a typical oxidative stress
response, consisting of diminished GSH relative to GSSG, decreased
potential to reduce protein-SSG mixed disulfide bonds (type 1 thiol
redox switch) or protein-SS-protein disulfide bonds (type 2 thiol
redox switch), and a +10 mV change in GSSG/2GSH reduction potential.
In contrast, mitochondria showed a rise in reduction state, consisting
of increased GSH relative to GSSG, increases in type 1 and type 2
thiol redox switches, and a -25 mV change in GSSG/2GSH reduction
potential. Comparing Ahr(-/-) knock-out and wild-type mice, we found
that TCDD-induced thiol changes in both cytosol and mitochondria were
dependent on the aromatic hydrocarbon receptor (AHR). GSH was rapidly
taken up by mitochondria and stimulated succinate-dependent H2O2
production. A linear dependence of H2O2 production on the reduction
potential for GSSG/2GSH exists between -150 and -300 mV. The TCDD-
stimulated increase in succinate-dependent and thiol-stimulated
production of reactive oxygen paralleled a four-fold increase in
formamidopyrimidine DNA N-glycosylase (FPG)-sensitive cleavage sites
in mitochondrial DNA, compared with a two-fold increase in nuclear
DNA. These results suggest that TCDD produces an AHR-dependent
oxidative stress in mitochondria, with concomitant mitochondrial DNA
damage mediated, at least in part, by an increase in the mitochondrial
thiol reduction state. PMID: 15883162
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