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研究生:高基富
研究生(外文):Chi-fu Kao
論文名稱:(1)以穩定同位素稀釋氣相層析質譜法同時分析人體尿液中乙烯基胞嘧啶與乙烯基腺嘌呤的含量.(2)以氣相層析質譜法分析3-乙基腺嘌呤.
論文名稱(外文):(1) Simultaneous Analysis of 3,N4-Ethenocytosine and 1,N6-Ethenoadenine in Human Urine by Isotope Dilution Gas Chromatography Mass Spectrometry.(2) Analysis of 3-Ethyladenine by GC-MS.
指導教授:陳皓君
指導教授(外文):Hauh-jyun Chen
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學所
學門:自然科學學門
學類:化學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:95
語文別:中文
論文頁數:123
中文關鍵詞:氣相層析質譜儀去氧核醣核酸之加成產物
外文關鍵詞:GC-MSDNA adducts
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(1). 乙烯基胞嘧啶 (3,N4-ethenocytosine, εCyt)與乙烯基腺嘌呤(1,N6-ethenoadenine, εAde)皆是環狀乙烯基加成產物,它可由體內的DNA與外來的致癌物反應形成,或與體內脂質過氧化所形成的化學物質反應生成。這些DNA加成產物可以經由不同的人體修復酵素從組織切除排至體液中,如尿液。我們實驗室在2001年及2003年分別發表了以同位素稀釋氣相層析負離子化學游離質譜法 (GC/NICI/MS)分析εCyt與εAde的方法,也比較吸煙者與非吸煙者尿液中εCyt與εAde的含量,吸煙者的尿液中平均而言含有較多的此類加成產物,因為其氧化壓力較高所致,然而在一個樣品中只單獨分析εCyt或εAde。我們曾經嘗試在GC-MS上合併分析此二加成產物,但是因為樣品中基質複雜使訊號背景較高,會影響εAde之定量。所以在衍生化與GC-MS步驟採取個別處理以及分析εCyt與εAde。在尿液中同時加入這兩個穩定的同位素做內標準物,經由C18-OH固相萃取管柱,分別收下εCyt與εAde,接著個別以親電性衍生化試劑 (PFB-Br)衍生,再以Si-OH固相萃取管柱純化,最後以GC-MS分別分析樣品中的εCyt與εAde,以準確量測尿液中的含量。此研究之目的是在同一尿液樣品中,同時分析εCyt與εAde,並比較性別與此二加成產物的關係,結果為尿液中εAde的含量以肌酸酐含量校正後與性別有統計上的關連,但是εCyt則無此關連。
(2). 香菸中含有超過四千種的化學物質,這些物質中含有烷化劑如:氯甲烷、亞硝基二甲胺等,其中也有一些化學物質會導致具反應性的含氧物種之生成。研究顯示抽煙會導致尿液中的3-甲基腺嘌呤及3-乙基腺嘌呤含量增加,而3-甲基腺嘌呤約有90%以上的含量與食物之攝取有很大的關係,但是尿液中3-乙基腺嘌呤的含量幾乎不受飲食差異的影響,並且研究顯示尿液中3-乙基腺嘌呤的含量小於1 nmol/day。所以我們希望開發以GC/NICI/MS量測尿液中3-乙基腺嘌呤之含量的方法。我們嘗試了幾個衍生化的方法,如:醯化 (acylation)或烷化 (alkylation),最後則成它a將3-乙基腺嘌呤 (3-EA)和七氟丁酸酐 (HFBA)進行衍生化反應並合成出HFB-3-EA,但是它並不穩定而且容易受水氣的影響而被分解。而以氣相層析負離子化學游離質譜法分析時,靈敏度又很低,限制了此方法的應用,因此未來還需要進一步開發更穩定、更靈敏的衍生化方法!偵測這些尿液中的3-alkylAde是非侵入性量測DNA損害的分析方法,這也可以作為暴露於烷化致癌物之生化指標。
(1). 3,N4-Ethenocytosine (eCyt) and 1,N6-ethenoadenine (eAde) are exocyclic DNA adducts known to derive from exogenous carcinogens as well as endogenous lipid peroxidation. These mutagenic DNA adducts can be repaired by base excision repair enzymes and excreted into biological fluids, such as urine. Our laboratory has reported two methods for independent analysis of eCyt and eAde in human urine using stable isotope dilution gas chromatography/negative ion chemical ionization/mass spectrometry (GC/NICI/MS). Levels of these two adducts were found to be significantly higher in smokers than in nonsmokers. The aim of this study is to analyze eCyt and eAde simultaneously in the same urine sample by a single GC/NICI/MS assay. The correlation between levels of these urinary DNA adducts and sex is also evaluated. When eCyt and eAde were combined for analysis by GC/NICI/MS, the complex matrix in urine samples increased the background level and affected quantification of eAde. Alternatively, eCyt and eAde were collected separately from C18-OH SPE column after addition of their isotopomers to urine. Electrophore-labeling of eCyt and eAde and post-derivatization cleanup steps were also performed separately before GC/NICI/MS analysis. This modified assay ensures accurate quantification of urinary eCyt and eAde. The result showed statistically significant correlation between gender and urinary eAde , but not eCyt, levels nornalized by creatinine contents.(2). Tobacco smoke contains over 4,000 compounds, which includes alkylating agents, such as methylchloride and nitrosamines, and some of them generate the formation of ROS. According to the literature, exposure to tobacco smoke resulted in increased levels of urinary 3-methyladenine (3-MeAde) and 3-ethyladenine (3-EtAde). Recent studies indicate that more than 90% of the background level of 3-MeAde in human urine is due to the presence of preformed 3-MeAde in foodstuffs. In contrast, 3-EtAde was not only excreted at low levels (<1 nmol/day) but was also very slightly affected by diet. In this study, we try to develop an analytical method which can quantify 3-EtAde in urine based on gas chromatography/ negative ion chemical ionization/ mass spectrometry (GC/NICI/MS). We attempted to derivatize 3-EtAde by acylation or alkylation. Nevertheless, after electrophore-labeling by heptafluorobutyric anhydride (HFBA), the product heptafluorobutyrated 3-ethyladenine (HFB-3-EA), was not stable and with low sensitivity by GC/NICI/MS. It limited the analytical method to be useful. A more stable and more sensitive approach for 3-EtAde derivatization is needed. From the biomonitoring point of view, urinary excretion of released 3-alkylAde can serve as the basis of a non-invasive biomarker for measuring DNA damage following exposure to alkylating carcinogens.
目錄 Ⅰ
圖表目錄 Ⅳ
附圖目錄 Ⅶ

第一部份 以穩定同位素稀釋氣相層析質譜法同時分析人體尿液中乙烯基胞嘧啶與乙烯基腺嘌呤的含量 1
中文摘要 2
英文摘要 3
1-1. 緒論 4
1-1-1. DNA加成產物對生物體的影響 4
1-1-2. 乙烯基加成產物的來源 6
1-1-3. DNA加成產物的生化意義 14
1-1-4. 負離子化學游離質譜法 17
1-1-5. 研究動機與背景 19
1-2. 實驗部分 22
1-2-1. 儀器 22
1-2-2. 材料 22
1-2-3. 藥品 23
1-2-4. 合成同位素標籤的εAde與εCyt 24
1-2-5. HPLC的分析條件 24
1-2-6. 氣相層析質譜儀系統條件 25
1-2-7. 尿液中乙烯基胞嘧啶與乙烯基腺嘌呤之分析 25
1-2-7-1. 利用C18-OH固相萃取管柱收集0.1毫升人體尿液中的εCyt與εAde之條件 27
1-2-7-2. PFB-εCyt與PFB-εAde的衍生化反應的條件 28
1-2-7-3. Si固相萃取PFB-εCyt與PFB-εAde的條件 29
1-2-7-4. 利用氣相層析儀搭配負離子化學游離質譜儀偵測人體尿液中εCyt與εAde之含量 30
1-3. 實驗結果 32
1-3-1. 以C18-OH SPE收集人體尿液中εCyt與εAde之方法確立 32
1-3-2. 以Si SPE收集PFB-εCyt與PFB-εAde之方法最佳化 32
1-3-3. 利用GC/NICI/MS法量測人體尿液中εCyt與εAde的含量 33
1-4. 討論 43
1-5. 結論 48
第二部份 以氣相層析質譜法分析3-乙基腺嘌呤 50
中文摘要 51
英文摘要 52
2-1. 緒論 53
2-2 實驗部分 58
2-2-1. 藥品 58
2-2-2. 儀器 58
2-2-3. 材料 59
2-2-4. 高效能液相層析儀搭配光電二極體陣列式偵檢器的分析條件 60
2-2-5. 氣相層析質譜儀系統條件 61
2-2-6. 實驗步驟 62
2-2-6-1. 合成標準品乙基腺嘌呤 62
2-2-6-2. 製作3-乙基腺嘌呤的定量曲線 62
2-2-6-3. PFB-Br和3-乙基腺嘌呤之衍生化反應 63
2-2-6-4. 醋酸酐和3-乙基腺嘌呤之衍生化反應 63
2-2-6-5. PFB-Br和乙醯-3-乙基腺嘌呤之衍生化反應 64
2-2-6-6. 七氟丁酸酐和3-乙基腺嘌呤之衍生化反應 65
2-2-6-7. 以Si SPE收集純化HFB-3EA之條件 65
2-2-6-8. 以GC/NICI/MS分析HFB-3-EA之條件 66
2-3. 實驗結果與討論 67
2-3-1. 合成3-乙基腺嘌呤結構之確立 67
2-3-2. 3-乙基腺嘌呤的HPLC定量曲線 69
2-3-3. PFB-Br和3-乙基腺嘌呤衍生化之結果 69
2-3-4 醋酸酐和3-乙基腺嘌呤衍生化之結構確立 70
2-3-5. 七氟丁酸酐(HFBA)和3-乙基腺嘌呤衍生化之結構確立 72
2-3-6. Si-SPE純化HFB-3-EA的分佈條件確立 73
2-3-7. 以氣相層析負離子化學游離質譜法分析3-乙基腺嘌呤之結果 74
2-4. 結論 75
參考文獻 76
附圖 91
中英對照表 111
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