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標題: S-Adenosylhomocysteine enhances DNA damage through increased beta-amyloid formation and inhibition of the DNA-repair enzyme OGG1b in microglial BV-2 cells
作者: Lin, H.C.
Song, T.Y.
Hu, M.L.
關鍵字: S-Adenosylhomocysteine;beta-Amyliod;DNA damage;8-oxoG-DNA;glycosylases I;Hypomethylation
Project: Toxicology
期刊/報告no:: Toxicology, Volume 290, Issue 2-3, Page(s) 342-349.
S-Adenosylhomocysteine (SAH) is a risk factor for neurodegenerative diseases such as Alzheimer's disease, for which beta-Amyliod (A beta) formation is a major risk factor. We recently showed that SAH increases A beta formation in mouse microglial BV2 cells. Here, we show that incubation of BV2 cells with SAH (0-500 nM) for 6-24 h sequentially increased A beta formation, ROS and DNA damage measured as 8-oxo-deoxyguanosine (8-oxo-dG) levels. Pre-incubation of BV2 cells with 20 mu M beta-secretase inhibitor IV for 30 min followed by incubation with SAH (500 nM) markedly decreased A beta formation and 8-oxo-dG levels. Treatment with SAH for 24 h concentration-dependently inhibited DNA methyltransferase (DNMT1) activity and inhibited DNMT1 binding to Sp1 site of 8-oxoG-DNA glycosylases I (OGG1) promoter and OGG1 protein and mRNA expression at 24 h: the latter effect was attributed to hypomethylation of the OGG1 gene promoter, because pre-incubation of cells with betaine (1.0 mM for 30 min) markedly prevented the inhibition of OGG1 protein expression induced by SAH. Overall, we demonstrate that SAH increases DNA damage in BV-2 cells possible by increased A beta formation leading to increased formation of ROS. Furthermore, the DNA damage is enhanced by SAH through inhibition of DNMT1 activity and hypomethylation of OGG1 gene promoter. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
ISSN: 0300-483X
DOI: 10.1016/j.tox.2011.10.016
Appears in Collections:食品暨應用生物科技學系

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