Proton pump inhibitors suppress iNOS-dependent DNA damage in Barrett鈥檚 esophagus by increasing Mn-SOD expression

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• 作者：Raynoo Thanan^a ; ^b ; Ning Ma^c ; Katsunori Iijima^d ; Yasuhiko Abe^d ; Tomoyuki Koike^d ; Tooru Shimosegawa^d ; Somchai Pinlaor^e ; Yusuke Hiraku^b ; Shinji Oikawa^b ; Mariko Murata^b ; Shosuke Kawanishi^a ; ^{kawanisi@suzuka-u.ac.jp}
• 关键词：Barrett&rsquo ; s esophagus ; 8-Nitroguanine ; Oxidative stress ; Proton pump inhibitors ; Antioxidants
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2012
• 期刊代码：159_0006291x
• 类别：bio
• 出版时间：4 May, 2012
• 卷：421
• 期：2
• 页码：280-285
• 文件大小：881 K

摘要

Barrett鈥檚 esophagus (BE), an inflammatory disease, is a risk factor for Barrett鈥檚 esophageal adenocarcinoma (BEA). Treatment of BE patients with proton pump inhibitors (PPIs) is expected to reduce the risk of BEA. We performed an immunohistochemical study to examine the formation of nitrative and oxidative DNA lesions, 8-nitroguanine and 8-oxo-7,8-dihydro-2鈥?deoxygaunosine (8-oxodG), in normal esophageal, BE with pre- and post-treatment by PPIs and BEA tissues. We also observed the expression of an oxidant-generating enzyme (iNOS) and its transcription factor NF-魏B, an antioxidant enzyme (Mn-SOD), its transcription factor (Nrf2) and an Nrf2 inhibitor (Keap1). The immunoreactivity of DNA lesions was significantly higher in the order of BEA > BE > normal tissues. iNOS expression was significantly higher in the order of BEA > BE > normal tissues, while Mn-SOD expression was significantly lower in the order of BEA < BE < normal tissues. Interestingly, Mn-SOD expression and the nuclear localization of Nrf2 were significantly increased, and the formation of DNA lesions was significantly decreased in BE tissues after PPIs treatment for 3-6 months. Keap1 and iNOS expression was not significantly changed by the PPIs treatment in BE tissues. These results indicate that 8-nitroguanine and 8-oxodG play a role in BE-derived BEA. Additionally, PPIs treatment may trigger the activation and nuclear translocation of Nrf2 resulting in the expression of antioxidant genes, leading to DNA damage suppression. These DNA lesions can be useful biomarkers to predict both the risk of BEA and the efficacy of PPIs treatment to prevent BEA in BE patients.