臺灣博碩士論文加值系統

人類暴露於環境中外來的化學物質以及體內生成之具反應性物質的破壞會導致體內DNA鹼基產生共價性的修飾，稱為DNA加成產物(DNA adducts)，它在多階段性的致癌過程中扮演一個關鍵性的角色，是導致細胞癌化的起始步驟。假如DNA加成產物沒有被體内自身修復機制所修復，這些修飾過的DNA鹼基則會在DNA複製過程中產生鹼基配對錯誤，導致基因突變，最終發展成癌症。由於生物體內存在對受損DNA的切除修復酵素，而被修復後的DNA加成產物會流至體液(biological fluids)，如尿液或血液。在此研究中，我們發展出一套具有高靈敏度及高特異性的奈升流速液相層析奈電噴灑游離串聯質譜法(nanoLC-NSI-MS/MS)，在高選擇反應追蹤(H-SRM)模式下搭配穩定同位素稀釋法同時量測人類尿液中1,N6-乙烯基腺嘌呤(1,N6-ethenoadenine；εAde)、3,N4-乙烯基胞嘧啶(3,N4-ethenocytosine；εCyt)、1,N2-乙烯基鳥糞嘌呤(1,N2-ethenoguanine；1,N2-εGua)、7-乙基鳥糞嘌呤(7-ethylguanine；7-EtG)、8-羥基-2’-去氧鳥糞嘌呤核苷(8-hydroxy-2’-deoxyguanosine；8-OH-dG)與古丁尼(cotinine；COT)之含量，尿液樣品前處理只需要經過Strata-X逆相固相萃取管柱純化，且不需要經過衍生化的步驟。目前已量測了13個人類尿液樣品，在5個吸菸者尿液樣品中所偵測到的εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG、COT平均濃度分別為171.2 ± 77.1 pg/mL、285.8 ± 193.5 pg/mL、104.0 ± 61.2 pg/mL、110.1 ± 64.6 pg/mL、3.38 ± 1.14 ng/mL、784.8 ± 536.3 ng/mL；而在8位非吸菸者尿液中所偵測到的εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG、COT平均濃度分別為85.2 ± 144.1 pg/mL、202.3 ± 247.3 pg/mL、31.5 ± 31.6 pg/mL、56.6 ± 68.5 pg/mL、2.31 ± 2.35 ng/mL、0.47 ± 0.43 ng/mL。希望藉此分析方法可以比較出εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG及COT與癌症的相關性，以此做為癌症風險評估的指標。

Exposure to environmental exogenous chemicals and endogenous reactive species in human can lead to the formation of structurally modified DNA bases (DNA adducts), which play a key role on multi-stage carcinogenesis process, and are the initial step of carcinogenesis. If DNA adducts have not been repaired by the body, these modified DNA bases could mispair by base to base, and lead to mutation during DNA replication, and develop into cancer eventually. These promutagenic DNA adducts are excised by base excision repair and nucleotide excision repair mechanisms and they are excreted into urine or blood as adducted bases and the nucleosides. In this report, we have developed an assay of high sensitivity and high specificity for simultaneous quantification of the five DNA adducts and cotinine by isotope dilution nanoflow liquid chromatography-nanospray ionization-tandem mass spectrometry (nanoLC-NSI/MS/MS)in human urine. Sample purification in urine before analysis by MS only requires a Strata-X reversed phase solid phase extraction column. The urine concentration of εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG and COT in 5 smokers are 171.2 ± 77.1 pg/mL、285.8 ± 193.5 pg/mL、104.0 ± 61.2 pg/mL、110.1 ± 64.6 pg/mL、3.38 ± 1.14 ng/mL and 784.8 ± 536.3 ng/mL, respectively；those in 8 nonsmokers are 85.2 ± 144.1 pg/mL、202.3 ± 247.3 pg/mL、31.5 ± 31.6 pg/mL、56.6 ± 68.5 pg/mL、2.31 ± 2.35 ng/mL and 0.47 ± 0.43 ng/mL, respectively. This highly sensitive and specific assay based on stable isotope dilution nanoLC-NSI/MS/MS assay provides a useful assay in measuring etheno、ethylpurine and oxidative adducts as noninvasive biomarkers in cancer risk ssessment.

目錄 I
圖表目錄 IV
附圖目錄 VII
以穩定同位素稀釋奈升流速液相層析奈電噴灑游離串聯質譜法同時定量人類尿液中五種DNA加成產物與古丁尼 1
中文摘要 2
Abstract 4
第一章 緒論 6
1-1 核醣核酸之簡介 6
1-2 DNA加成產物的影響與種類 8
1-3 外環類乙烯基加成產物的來源與生化意義 13
1-4 烷化類鹼基加成產物的來源與生化意義 16
1-5 氧化鹼基加成產物的來源與生化意義 18
1-6 研究背景與文獻回顧 19
1-7 研究目的 23
第二章 實驗部分 25
2-1 實驗藥品 25
2-2 實驗儀器 25
2-3 實驗材料 26
2-4 高效能液相層析儀搭配光電二極體陣列式偵檢器分析條件 27
2-5 利用Strata-X固相萃取管柱收集εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG與COT標準品 27
2-6 奈電噴灑游離所使用的尖端毛細管製作過程 28
2-7 奈升流速液相層析奈電噴灑游離串聯式質譜儀(nanoLC-NSI-MS/MS)分析條件 28
2-8 尿液樣品前處理 31
2-9 校正曲線 31
2-10 精密度 32
2-11 準確度 32
2-12 利用Strata-X固相萃取管柱收集人類尿液中之εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG與COT 33
第三章 實驗結果與討論 34
3-1 利用Strata-X固相萃取管柱收集εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG與COT標準品 34
3-2 εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG、COT及其穩定同位素內標準品之定性質譜圖譜 38
3-3 高選擇反應追蹤(H-SRM)條件確認 39
3-4 校正曲線與偵測極限 39
3-5 精密度 42
3-6 準確度 43
3-7 利用奈升流速液相層析奈電噴灑游離串聯式質譜儀分析人類尿液中的εAde、εCyt、1,N2-εGua、7-EtG、8-OH-dG與COT 44
第四章 結論 56
第五章 參考文獻 58
第六章 附圖 71

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