臺灣博碩士論文加值系統

背景：Human 8-oxoguanine-DNA glycosylase (hOGG1) 是人體中主要負責將7,8-dihydro-8-oxo-2’-deoxyguanosine (8-oxodG) 移除的酵素。8-oxodG是dG被氧化的衍生物，亦為生物體內最常見的氧化性鹼基之一。在細胞系統中，三價無機砷 (As3+ )、香菸煙霧提取物 (CSE) 與甲基乙二醛 (MG) 已知皆會誘導活性氧物種 (reactive oxygen species, ROS) 的產生，而且As3+與CSE也會降低hOGG1的修補活性，造成8-oxodG的過量累積。然而，As3+、CSE與MG是否直接影響hOGG1的酵素活性，以及可能的作用機制，目前都仍不清楚。目的：因此，本研究利用人類血管內皮類似細胞 (ECV304 cells)，探討As3+、CSE與MG 誘發氧化性DNA傷害之可能機制。方法：以內切酶活性測試法分析酵素活性；以結晶紫染色法計算細胞總數，觀察細胞增生情形；以DCHF-DA染色法觀察細胞內ROS生成濃度；以8-oxodG免疫螢光顯微測定法觀察細胞內8-oxodG的含量；以西方墨點法測量蛋白質表現量。結果：當hOGG1與Fpg和As3+ (0.1 – 1000 µM)、CSE (5 – 25%)、過氧化氫 (1 – 15 mM) 或氧化態榖胱甘肽 (GSSG, 0.2 – 5 mM) 共處理下，hOGG1與Fpg的酵素活性均未受影響，然而MG (0.5 – 4 mM) 則以劑量效應抑制Fpg的活性 (P<0.05)，然而hOGG1的酵素活性則不受MG影響；另外，也發現N-acetyl-L-cysteine (NAC, 0.2 – 5 mM)、glutathione (GSH, 0.2 – 5 mM) 與硫酸銅 (1 – 1000 µM) 會抑制hOGG1與Fpg的活性 (P<0.01)。當ECV304細胞以As3+ (0.25 – 10 µM) 處理24小時後，會誘發細胞內ROS上升，同時5與10 µM As3+處理24小時後，也明顯增加細胞內8-oxodG的產生 (P<0.05)，而且也會些微增加OGG1/2蛋白質表現量 (P<0.05)；但只在以CSE (2.5 – 10%) 處理24小時下，細胞內ROS和8-oxodG並未上升，而且OGG1/2蛋白表現量甚至低於對照組 (P<0.01；P<0.001)。結論：綜合上述結果，As3+、CSE與MG不會直接抑制hOGG1的酵素活性。細胞實驗中，As3+透過ROS誘發8-oxodG，同時OGG1蛋白質表現量也會增加，將可強化細胞修補8-oxodG的作用。而CSE不會造成ECV304細胞內ROS和8-oxodG的產生，也會使OGG1/2蛋白質表現量下降。

OGG1 is the main base excision repair protein that removes 8-oxodG from DNA. Previous studies have shown that sodium arsenite (As3+), cigarette smoke extract (CSE), and methylglyoxal (MG) can significantly induced DNA damage, including 8-oxodG in different human cell lines. And, the intracellular reactive oxygen species (ROS) generation is mainly responsible for their induction of 8-oxodG. However, the suppression of OGG1 expression or activity by As3+, CSE and MG treatments are still unknown. Therefore, the purpose of this study was to determine the possible deleterious effects of As3+, MG and CSE on gene expression and enzyme activity of OGG1. The expression level and enzyme activity of OGG1 protein were detected by Western blot and endonuclease activity assay, respectively. The levels of intracellular ROS and 8-oxodG of As3+, CSE and MG-treated cells were also detected by DCHF-DA assay using a multi-well fluorescence plate reader and immunofluorescence staining. The results showed that none of As3+ (0.1 – 1000 µM), CSE (5% – 25%) and H2O2 (1 – 15 mM) could inhibit directly the enzyme activities of FPG and hOGG1 in vitro. Surprisingly, MG (0.5 – 4 mM) could potently inhibit the enzyme activity of FPG with a dose-dependent manner (P<0.05), but it did not influence the emzyme activity of hOGG1. Interestingly, thiol antioxidants (NAC and GSH) (0.2 – 5 mM) and Cu2+ (1 – 1000 µM) also significantly inhibited the enzyme activity of both FPG and hOGG1 (P<0.01), but GSSG (0.2 – 5 mM) did not affect the FPG and hOGG1 activities. ECV304 cells treatment with As3+ (0.25 – 10 µM) could increase intracellular ROS levels. After treatment with 5 and 10 µM As3+, nuclear 8-oxodG levels were increased (P<0.05). In addition, there was a slight increase (P<0.05) in the intracellular OGG1/2 protein expression. However, it could neither induce ROS nor reduce OGG1/2 protein expression (P<0.01) after ECV304 was treated with CSE (5% - 25%) for 24 hours. Taken together, these results suggest that As3+-induced 8-oxodG formation may not be caused by a direct inhibition of hOGG1 activity but through its effect of increasing the level of ROS in ECV304 cells. In vitro, the activity of purified Fpg and hOGG1 proteins inhibited by thiol containing compounds (GSH and NAC) also suggests that cellular GSH may be involved in the regulation of the DNA repair enzyme hOGG1 in human cells.

縮寫表 v
中文摘要 vi
英文摘要 viii
第一章文獻回顧 1
一. 活性氧物種 1
二. 8–側氧鳥糞嘌呤 2
三. 人類8 –側氧基鳥糞嘌呤去氧核糖核酸糖基解酶 3
1. OGG1簡介 3
2. hOGG1與8-oxodG修補路徑 5
3. hOGG1與AMPK路徑的關係 6
4. hOGG1與疾病的關係 7
四. 砷化物 8
1. 砷化物的簡介 8
2. 砷化物與氧化壓力 9
3. 砷化物與疾病的關係 9
五. 香菸煙霧提取物 11
1. 香菸的簡介 11
2. 香菸煙霧提取物與氧化壓力 11
3. 香菸煙霧提取物與疾病的關係 12
六. 甲基乙二醛 13
1. 甲基乙二醛的簡介 13
2. 甲基乙二醛與氧化壓力 15
3. 甲基乙二醛與疾病的關係 16
第二章 研究動機與架構 17
一.動機 17
二.架構 18
第三章 材料與方法 19
一.材料 19
二.方法 25
1. 香菸煙霧提取物的製備 25
2. 細胞培養 25
3. 細胞增生能力分析 26
4. 細胞內氧化壓力分析法 27
5. 8-oxodG免疫螢光顯微測定法 28
6. 蛋白質定量法 29
7. 蛋白質電泳法 29
8. 西方墨點法 31
9. 內切酶活性測試法 31
10. 蛋白質結構分析 36
11. 統計分析 36
第四章 結果 37
一. 建立內切酶活性測試法 37
二. 三價無機砷、香菸煙霧提取物、甲基乙二醛、硫酸銅與過氧化氫對Fpg與hOGG1酵素活性之影響 37
三. 含硫抗氧化劑對Fpg與hOGG1酵素活性之影響 40
四. 三價無機砷、香菸煙霧提取物與甲基乙二醛對ECV304細胞增生及形態的影響 41
五. 三價無機砷與香菸煙霧提取物對ECV304細胞內氧化壓力的形成 42
六. 三價無機砷與香菸煙霧提取物對ECV304細胞誘發8-oxodG的形成 43
七. 三價無機砷、香菸煙霧提取物與甲基乙二醛誘導hOGG1的蛋白質表現量 44
八. pp242對ECV304細胞內hOGG1蛋白質表現量的影響 45
九. 全細胞溶解物的OGG1酵素活性測試 46
十. NaOH對hOGG1酵素活性的影響 47
第五章 討論 48
第六章 結論 57
第七章 圖表 59
圖一. Fpg與hOGG1酵素活性標準曲線 60
圖二. 三價無機砷、香菸煙霧提取物、甲基乙二醛、硫酸銅與過氧化氫對Fpg與hOGG1酵素活性之影響 63
圖三. 含硫抗氧化劑對Fpg與hOGG1酵素活性之影響 66
圖四. 三價無機砷、香菸煙霧提取物與甲基乙二醛對ECV304細胞增生及形態的影響 69
圖五. 三價無機砷與香菸煙霧提取物在ECV304細胞誘發氧化壓力的形成 71
圖六. 三價無機砷與香菸煙霧提取物在ECV304細胞誘發8-oxodG的形成 75
圖七. 三價無機砷、香菸煙霧提取物與甲基乙二醛對ECV304細胞內hOGG1蛋白質表現量的影響 78
圖八. pp242對ECV304細胞內hOGG1蛋白質表現量的影響 79
圖九. 全細胞溶解物的內切酶活性測試 81
圖十. NaOH增加hOGG1的AP lyase活性 82
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