title: Proton pump inhibitors suppress iNOS-dependent DNA damage in Barrett's esophagus by increasing Mn-SOD expression.
abstract: Barrett's esophagus (BE), an inflammatory disease, is a risk factor for Barrett's 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'-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-κB, 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 3-6months. 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie 513-8670, Japan.
authors.forename: Raynoo
authors.initials: R
authors.lastname: Thanan
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Abe
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Koike
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.forename: Somchai
authors.initials: S
authors.lastname: Pinlaor
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hiraku
authors.forename: Shinji
authors.initials: S
authors.lastname: Oikawa
authors.forename: Mariko
authors.initials: M
authors.lastname: Murata
authors.forename: Shosuke
authors.initials: S
authors.lastname: Kawanishi
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D001471:Barrett Esophagus / Q000201:enzymology* / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000096:biosynthesis; D004947:Esophagus / Q000201:enzymology; D006147:Guanine / Q000031:analogs & derivatives / Q000096:biosynthesis; D006801:Humans; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000096:biosynthesis; D016328:NF-kappa B / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D054328:Proton Pump Inhibitors / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000096:biosynthesis*
chemical_list: C095838:8-nitroguanine; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495635:NFE2L2 protein, human; D054328:Proton Pump Inhibitors; D006147:Guanine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D003849:Deoxyguanosine