Dysfunction of Nrf2 decreases KBrO3-induced oxidative DNA damage in Ogg1-null mice.
Transcription factor Nrf2 regulates production of antioxidants and protects cells from oxidative/electrophilic stresses. Paradoxically, glutathione, one of the Nrf2-regulated antioxidants, has been assumed to promote genotoxicity of KBrO3. To address this glutathione hypothesis, we examined roles Nrf2 plays in the cellular defense against KBrO3-induced oxidative damage using Nrf2-/-, Ogg1-/- and Nrf2::Ogg1 double knockout mice. We found that upon KBrO3 treatment Nrf2::Ogg1 double knockout animals suffered from severe kidney damage, but unexpectedly the double knockout mice accumulated lower level of 8-hydroxyguanine than Ogg1-/- mice. Thus, KBrO3-induced nephrotoxicity appears not to depend on the formation of 8-hydroxyguanine. Our data also indicate that both the KBrO3-induced nephrotoxicity and formation of 8-hydroxyguanine are Nrf2-controlled processes, but the changes of the glutathione level are Nrf2-independent. Based on these results we conclude that glutathione is a minor part of the mechanism promoting genotoxicity of KBrO3 in Ogg1 knockout mice.
Jałoszyński
Paweł
P
Center for Tsukuba Advanced Research Alliance and JST-ERATO Environmental Response Project, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8577, Japan.
Murata
Soichiro
S
Shinkai
Yasuhiro
Y
Takahashi
Satoru
S
Kumagai
Yoshito
Y
Nishimura
Susumu
S
Yamamoto
Masayuki
M
D000818:Animals; D001959:Bromates / Q000494:pharmacology*; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D045647:DNA Glycosylases / Q000378:metabolism*; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects
D001959:Bromates; D051267:NF-E2-Related Factor 2; C019536:potassium bromate; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse