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研究生:王薏菁
研究生(外文):Wang, Yi-Ching
論文名稱:以穩定同位素稀釋毛細管液相層析奈電噴灑游離串聯質譜法量測(1)人類白血球DNA中之乙基胸腺嘧啶核苷加成產物(2)人類尿液中的丙烯醛和反式丁烯醛之N-乙醯基半胱胺酸代謝產物含量
論文名稱(外文):Simultaneous Quantification of (1) Three Ethyl-Thymidine Adducts in Human White Blood Cells (2) 3-Hydroxypropylmercapturic Acid and 3-Hydroxy-1-methylpropylmercapturic Acid in Human Urine by Stable Isotope Dilution Capillary Liquid Chromatography /Nanospr
指導教授:陳皓君
指導教授(外文):Chen, Hauh-Jyun Candy
口試委員:陳皓君王少君李茂榮
口試委員(外文):Chen, Hauh-Jyun CandyWang, Shau-ChunLEE, Maw-Rong
口試日期:2011-07-22
學位類別:碩士
校院名稱:國立中正大學
系所名稱:化學暨生物化學研究所
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:2011
畢業學年度:99
語文別:中文
論文頁數:86
中文關鍵詞:穩定同位素毛細管液相層析奈電噴灑游離串聯質譜法乙基胸腺嘧啶核苷加成產物N-乙醯基半胱胺酸代謝產物
外文關鍵詞:Capillary Liquid Chromatography /Nanospray Ionization Tandem Mass Spectrometryadduct3-Hydroxypropylmercapturic Acid3-Hydroxy-1-methylpropylmercapturic Acid
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香煙中的烷基化試劑會與DNA鹼基上的氧原子和氮原子發生加成反應而形成DNA加成產物,進而使DNA突變甚至可能會導致癌症產生。動物研究顯示,當暴露在含有乙基化試劑的環境中,會形成O4-ethylthymidine (O4-edT),雖然含量在最初時並不多,但難被修復,會累積在體內,也有文獻顯示吸煙者特定組織與尿液中之DNA鹼基上的乙基化修飾加成產物含量高於非吸煙者。在此研究中,我們希望能發展出一分析方法用來評估組織DNA受到乙基化損害的程度,並希望可以比較出O2-edT、N3-edT及O4-edT與癌症的相關性,以此做為癌症風險評估的生化指標。我們分析經碘乙烷反應之小牛胸腺DNA,加入O2-edT、N3-edT及O4-edT的穩定同位素當內標準品,以酵素水解使DNA上的乙基加成產物脫落,通過逆相固相萃取管濃縮純化這三種乙基加成產物。以毛細管液相層析奈電噴灑游離串聯質譜法,在高選擇反應追蹤模式 (H-SRM) 下同時分析此DNA中的O2-edT、N3-edT及O4-edT。O2-edT測得之偵測極限為5 fg (18.5 amol),N3-edT和O4-edT測得之偵測極限為10 fg (37.0 amol)。毛細管液相層析質譜法具有高靈敏度,且可提供結構上資訊,奈電噴灑游離法可以提高游離的效率及靈敏度,而搭配同位素的內標準法定量,可提高分析方法的準確度。在經碘乙烷反應之小牛胸腺DNA中乙基加成產物的含量為在108個正常鹼基中分別有5.7個O2-edT、77.2個N3-edT和8.0個O4-edT。在9個吸煙者之白血球DNA中,108個正常核苷中有11.4 ± 23.4個O2-edT、12.8 ± 16.8個N3-edT及10.5 ± 21.7個O4-edT;在9個非吸煙者則有0.4 ± 1.3個O2-edT、9.0 ± 19.3個N3-edT及1.7 ± 4.1個O4-ed。由於在人類胎盤DNA中所測得的edT含量過低導致無法精確定量,因此希望針對edT的結構之五碳環上的OH基來做衍生化反應,來提升edT在質譜上的分析靈敏度。目前已利用結構類似的dT與edT和4種衍生化試劑來進行反應,但edT及dT的反應性不好,不容易進行衍生化反應。
O-Substitution by alkylating agents of cigarette smoke results in DNA adducts, which are considered to be major promutagenic lesion and may cause cancer formation. Animal studies indicated that, after exposure to ethylating agents, O4-ethylthymidine (O4-edT) was initially formed in very low levels, but it was poorly repaired and thus accumulated to biologically relevant levels. Studies also show that ethylated adducts in certain tissues and urine are higher in smokers than in nonsmokers. In this study, we have developed a highly sensitive and quantitative assay for simultaneous detection and quantification of O2-edT, N3-edT, and O4-edT adducts by isotope dilution capillary liquid chromatography nanospray ionization tandem mass spectrometry (capillary LC-NSI/MS/MS) under the highly selective reaction monitoring (H-SRM) mode. Typically, [13C10,15N2]O2-edT, [13C10,15N2]N3-edT, and [13C10,15N2]O4-edT were added to iodoethane-treated calf thymus, human placenta, or human leukocyte DNA as internal standards, and the mixture was subjected to enzyme hydrolysis to form the nucleosides. The edT adducts in DNA hydrolysate were enriched by a reversed phase solid-phase extraction column before analysis by capillary LC-NSI/MS/MS.The detection limits of O2-edT, N3-edT, and O4-edT injected on-column are 18.5 amol, 37.0 amol, and 37.0 amol, respectively. Levels of O2-edT, N3-edT, and O4-edT in iodoethane-treated calf thymus DNA are 5.7, 77.2 and 8.0 in 108 normal nucleotides, respectively, but none of these adducts are detected in human placental DNA. Levels of O2-edT, N3-edT, and O4-edT are 11.2 ± 23.4, 12.8 ± 16.8, 10.5 ± 21.7 in 108 normal nucleotides in smokers white blood cells (WBC) DNA (n=9), comparing with 0.4 ± 1.3, 9.0 ± 19.3, 1.7 ± 4.1 in nonsmokers WBC DNA (n=9). In order to increase the detection sensitivity, we try to derivatizate edT adducts. Four derivatization agents have been tried, but none of them are successful. The main reasons might be the poor and reactivity of edT and dT.
目錄
目錄 i
圖表目錄 v
附圖目錄 vi

第一部分 以穩定同位素稀釋毛細管液相層析奈電噴灑游離串聯質譜法量測
(1)人類白血球DNA中之乙基胸腺嘧啶核苷加成產物
英文摘要 2
中文摘要 3
第一章 緒論 4
1-1 簡介 4
1-2 烷基加成產物的來源 6
1-3 乙烷基DNA加成產物的生化意義 7
1-4 研究動機與背景 8
1-5 欲分析物之衍生化:增加分析靈敏度 10
第二章 實驗流程 14
2-1 藥品 14
2-2 儀器 14
2-3 材料 15
2-4 高效能液相層析儀搭配光電二集體陣列式偵檢器的分析條件 15
2-5 Capillary LC-NSI/MS/MS 系統分析條件 16
2-6 實驗步驟 17
2-6-1. EdT或[13C10,15N2]edT的合成 17
2-6-2. 利用C18-OH固相萃取管柱純化收集edT或[13C10,15N2]edT之標
準品 17
2-6-3. EdT的氫核磁共振光譜及碳13核磁共振光譜 18
2-6-4. 比較C18與C18-OH固相萃取管柱純化[13C10,15N2]edT效率 19
2-6-5. 血液前處理與萃取白血球DNA步驟 19
2-6-6. 碘乙烷與小牛胸腺DNA反應的方法 20
2-6-7. 酵素水解DNA過程 20
2-6-8. 利用C18-OH固相萃取管柱收集DNA水解完之edT的條件 22
2-6-9. 利用毛細管液相層析奈電噴灑游離串聯式質譜法分析DNA中的
O2-edT、N3-edT和O4-edT 22
2-6-10. Capillary LC-NSI/MS/MS校正曲線 22
2-6-11. 精確度(precision)和準確度(accuracy) 22
2-6-12. Di-propionyl ethyl-2’-deoxythymidine(propionyl edT)的合成、C18
固相萃取管柱純化及利用毛細管液相層析奈電噴灑游離串聯式質
譜法分析 23
2-6-13. Dansyl-dT的合成 23
2-6-14. Methylpyridinium-dT的合成 24
2-6-15. Nicotinyl-dT的合成 25
第三章 實驗結果與討論 26
3-1 EdT的合成與ESI-MS、1H NMR和 13C NMR鑑定結構 26
3-2 EdT的HPLC-UV molar response圖及穩定度 28
3-3 利用毛細管液相層析奈電噴灑游離串聯式質譜法分析DNA中的
O2-edT、N3-edT、O4-edT加成產物 28
3-4質譜分析DNA中的O2-edT、N3-edT、O4-edT加成產物 30
3-5. 比較C18與C18-OH固相萃取管柱純化[13C10,15N2]edT效率 30
3-6. 酵素方法比較 31
3-7. 偵測極限(LOD)、定量極限(LOQ)與校正曲線 32
3-8. 精確度(precision)和準確度(accuracy) 33
3-9. 分析經由碘乙烷反應之小牛胸腺DNA、人類胎盤DNA與人類白血
球DNA中的edT含量 34
3-10. Di-propionyl edT的合成及純化 36
3-11. Di-propionyl edT的穩定性和HPLC-UV molar response 37
3-12.質譜分析di-propionyl edT與偵測極限(Limit of detection, LOD) 37
3-13. Dansyl-dT的合成 38
3-14. Methylpyridinium-dT的合成 39
3-15 Nicotinoyl-dT的合成 40
第四章 結論 42

第二部分 以穩定同位素稀釋毛細管液相層析奈電噴灑游離串聯質譜法量測
(2)人類尿液中的丙烯醛和反式丁烯醛之N-乙醯基半胱胺酸代謝產
物含量
英文摘要 44
中文摘要 45
第五章 緒論 46
5-1.丙烯醛的介紹 46
5-2.反式丁烯醛的介紹 47
5-3.研究動機與背景 48
第六章 實驗流程 49
6-1. 藥品 49
6-2. 儀器 49
6-3. 材料 49
6-4.高效能液相層析儀搭配光電二集體陣列式偵檢器的分析條件 50
6-5. 實驗步驟 50
6-5-1. N-acetylcysteine的合成步驟 50
6-5-2. 3-HPMA的合成步驟 50
6-5-3. HMPMA的合成步驟 50
6-5-4.利用C18-OH固相萃取管柱純化收集3-HPMA 和HMPMA之標
準品 50
第七章 實驗結果與討論 52
7-1. N-acetylcysteine(NAC)的合成 52
7-2. 3-HPMA的合成步驟 52
7-3. HMPMA的合成步驟 52
第八章 結論 53
第九章 參考文獻 54


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