TY - JOUR
T1 - Dysfunction of Nrf2 decreases KBrO3-induced oxidative DNA damage in Ogg1-null mice
AU - Jałoszyński, Paweł
AU - Murata, Soichiro
AU - Shinkai, Yasuhiro
AU - Takahashi, Satoru
AU - Kumagai, Yoshito
AU - Nishimura, Susumu
AU - Yamamoto, Masayuki
PY - 2007/12/28
Y1 - 2007/12/28
N2 - 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.
AB - 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.
KW - 8-oxoguanine
KW - Bromate
KW - GSH
KW - Nrf2
KW - Ogg1
KW - Oxidative DNA damage
KW - Oxidative stress
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UR - http://www.scopus.com/inward/citedby.url?scp=36049035679&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2007.10.123
DO - 10.1016/j.bbrc.2007.10.123
M3 - Article
C2 - 17971305
AN - SCOPUS:36049035679
VL - 364
SP - 966
EP - 971
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 4
ER -