Dysfunction of Nrf2 decreases KBrO3-induced oxidative DNA damage in Ogg1-null mice
Dysfunction of Nrf2 decreases KBrO3-induced oxidative DNA damage in Ogg1-null mice
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DOI：
10.1016/j.bbrc.2007.10.123
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发表时间：
2007-12-28
影响因子：
3.1
通讯作者：
Yamamoto, Masayuki
中科院分区：
文献类型：
--
作者：
Jaloszynski, Pawel;Murata, Soichiro;Yamamoto, Masayuki
转录因子Nrf2调节抗氧化剂的产生，保护细胞免受氧化/亲电应激。矛盾的是，谷胱甘肽，nrt2调节的抗氧化剂之一，被认为促进KBrO3的遗传毒性。为了验证这一谷胱甘肽假说，我们使用Nrf2（-/-）、Ogg1（-/-）和Nrf2::Ogg1双敲除小鼠，研究了Nrf2在kbro3诱导的氧化损伤的细胞防御中所起的作用。我们发现，在KBrO3处理下，Nrf2::Ogg1双敲除小鼠遭受了严重的肾损伤，但出乎意料的是，双敲除小鼠积累的8-羟基鸟嘌呤水平低于Ogg1（-/-）小鼠。因此，kbro3诱导的肾毒性似乎不依赖于8-羟基鸟嘌呤的形成。我们的数据还表明，kbro3诱导的肾毒性和8-羟基鸟嘌呤的形成都是nrf2控制的过程，但谷胱甘肽水平的变化是nrf2独立的。基于这些结果，我们得出结论，谷胱甘肽是促进Ogg1敲除小鼠KBrO3遗传毒性机制的一小部分。(C) 2007爱思唯尔公司版权所有。
Transcription factor Nrf2 regulates production of antioxidants and protects cells from oxidative/electrophilic stresses. Paradoxically, glutathione, one of the Nrt2-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. (C) 2007 Elsevier Inc. All rights reserved.