臺灣博碩士論文加值系統

乙烯基DNA加成產物是由內生性或外生性物質引起DNA損傷的產物。在此研究中，我們發展了使用同位素稀釋液相層析電噴灑游離串聯質譜法去量測人類尿液中乙烯基腺嘌呤的含量。使用法分析乙烯基腺嘌呤標準品的偵測極限是2.0 pg，而尿液中乙烯基腺嘌呤濃度之定量極限為10 pg/mL。碰撞活化解離子離子質譜圖證明了尿液中乙烯基腺嘌呤的存在。我們使用此方析法鑑定了十八位健康的志願者24小時的尿液樣品中乙烯基腺嘌呤之含量，其結果與同位素稀釋氣相層析負離子化學游離質譜法相當一致。量測尿液中乙烯基腺嘌呤的含量可做為DNA氧化性損傷與以化學藥品預防癌症之研究的生物指標。
具反應性的含氮氧物種會與DNA反應生成8-硝基鳥糞嘌呤和8-硝基黃嘌呤，此二種硝基DNA加成產物因為會產生自發性去嘌呤作用，而在DNA上不穩定。我們利用血晶質和含血質的蛋白質搭配各種還原劑在生理條件下將8-硝基鳥糞嘌呤和8-硝基黃嘌呤還原成8-胺基鳥糞嘌呤和8-胺基黃嘌呤。血紅素搭配還原態硫辛酸還原效果是最佳的。我們也證實了血紅素可以還原經過硝基氯處理過的小牛胸腺DNA後所產生的8-硝基鳥糞嘌呤和8-硝基黃嘌呤。血晶質還原DNA上8-硝基鳥糞嘌呤的效果比含有相同莫爾數血質的血紅素還要好，顯示蛋白質會妨礙反應。此外，我們也證明了還原產物8-胺基鳥糞嘌呤在DNA上是穩定的。這些結果推論血質和生物抗氧化劑所組成的系統可以還原硝基DNA加成產物，代表著體內一種修飾DNA硝化反應的可能途徑。
調節粒腺體弁鄋熔茩M色素c容易受到過氧化亞硝酸根的攻擊。我們利用液相層析電噴灑游離質譜儀量測蛋白質的特定硝化位置，探討過氧化亞硝酸根硝化細胞色素c的選擇性。我們使用原始參考胜肽相對定量法探討不同濃度的具反應性的含氮氧物種對細胞色素c硝化位置的程度。活化碰撞解離的質譜圖可以證明此四個含有3-硝基酪胺酸的胜肽的形成。更進一步地，藉由Na2S2O4將3-硝基酪胺酸還原成3-胺基酪胺酸，再利用液相層析電噴灑游離串聯質譜儀分析可證實3-硝基酪胺酸的形成。

Etheno DNA adducts are promutagenic DNA lesions derived from exogenous as well as endogenous sources. In this report, a new assay based on isotope dilution liquid chromatography-electrospray ionization-tandem mass spectrometry is developed for the quantification of 1,N6-ethenoadenine (eAde) in human urine samples. The detection limit of eAde standard using LC-ESI-MS/MS is 2.0 pg, and the concentration quantification limit for urinary eAde is 10 pg/mL. The presence of eAde in human urine is confirmed by the collision- induced daughter ion spectrum. Using this assay, the levels of eAde in the 24-h urine samples from 18 healthy individuals are very good agreement with those obtained using isotope dilution gas chromatography-negative ion chemical ionization-mass spectrometry. The high specificity and simple sample pretreatment of this LC-ESI-MS/MS method render it a valuable tool in measuring eAde in the complex mixture of human urine.
The nitrated DNA adducts 8-nitroguanine (8NG) and 8-nitroxanthine (8NX) have been shown to derive from reactive nitrogen oxide species, but they are not stable in DNA since they undergo spontaneous depurination. We herein report that hemin and hemoproteins mediate reduction of 8NG and 8NX to their corresponding amino analogues in the presence of reducing agents under physiologically relevant conditions. The hemoglobin macromolecule reduces 8NG and 8NX formed in nitryl chloride-treated calf thymus DNA, as evidenced by the formation of the 8-aminopurines using reversed-phase HPLC with photodiode array detection. We also show that the reduction product 8-aminoguanine is persistent on DNA. These findings suggest that reduction of nitrated DNA by the heme/antioxidant system might represent a possible in vivo pathway to modify DNA nitration.
Cytochrome c, a mediator of mitochondrial function, represents an important potential target of peroxynitrite. In this study, we investigate the selectivity of cytochrome c nitration by peroxynitrite using liquid chromatography-electrospray ionization-mass spectrometry to quantify site-specific nitration of cytochrome c. We compared the extent of nitration in the trypsin digest of cytochrome c treated with various concentrations of nitrating systems by native reference peptides or parent peptides under selective ion monitoring mode. Characterization of the four 3-nitrotyrosine-containing peptides was achieved by their collision-induced dissociation (CID) spectra. Furthermore, reduction of the tryptic digest with Na2S2O4 showed 3-aminotyrosine formation by LC-ESI/MS/MS further confirmed the presence of 3-nitrotyrosine.

目錄 I
圖表目錄 VI
附圖目錄 VIII
英文摘要 XII
中文摘要 XIV

第一部分 以穩定同位素稀釋液相層析電噴灑游離串聯質譜法定量人類尿液中之乙烯基腺嘌呤 1

英文摘要 2
中文摘要 3
第一章 緒論 4
第二章 實驗流程 13
2-1. 藥品 13
2-2. 儀器 13
2-3. 材料 14
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 14
2-5. 液相層析電噴灑游離串聯質譜儀分析系統 14
2-6. 實驗步驟 15
2-6-1. 同位素乙烯基腺嘌呤合成 15
2-6-2. 尿液的前處理 16
2-6-3. 以C18-OH固相萃取管收集乙烯基腺嘌呤標準品 16
2-6-4. 以C18-OH固相萃取管收集1 mL人體尿液中的乙烯基腺嘌呤 17
2-6-5. 利用液相層析電噴灑游離串聯質譜法對人體尿液中乙烯基腺嘌呤進行定量 17
2-6-6. 製作定量線 18
2-6-7. 利用氣相層析負離子化學游離質譜法對人體尿液中乙烯基腺嘌呤進行定量 18
第三章 實驗結果與討論 20
3-1. 液相層析電噴灑游離串聯質譜法對於乙烯基腺嘌呤的分析 20
3-2. 偵測極限，校正曲線，精確度和準確度 23
3-3. 分析人類尿液中的乙烯基腺嘌呤含量 25
3-4. 比較氣相層析負離子化學游離質譜法和液相層析電噴灑游離串聯質譜法偵測尿液乙烯基腺嘌呤含量的相關性 28
第四章 結論 29
第五章 參考文獻 30
附圖 41

第二部分 含血質蛋白質搭配還原劑還原DNA上8-硝基嘌呤之研究 50

英文摘要 51
中文摘要 52
第一章 緒論 53
第二章 實驗流程 56
2-1. 藥品 56
2-2. 儀器 57
2-3. 材料 57
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 57
2-5. 實驗步驟 58
2-5-1. 過氧化亞硝酸根的合成及濃度測定 58
2-5-2. 8-硝基鳥糞嘌呤的合成 59
2-5-3. 8-硝基黃嘌呤的合成 59
2-5-4. 8-胺基鳥糞嘌呤的合成 59
2-5-5. 8-胺基黃嘌呤的合成 59

2-5-6. 含血質的蛋白質或化合物與反式-2,3-二羥基-1,4-二硫基丁烷對含硝基DNA加成產物的還原反應 60
2-5-6. 血紅素與各種抗氧化劑對含硝基DNA加成產物的還原反應 60
2-5-7. 對照組：實驗各種抗氧化劑對含硝基DNA加成產物的還原反應 60
2-5-8. 血紅素濃度對8-硝基鳥糞嘌呤或8-硝基黃嘌呤的還原效果影響 61
2-5-9. 在無氧的條件下對含8-硝基黃嘌呤進行還原反應 61
2-5-10. 血紅素與反式-二硫基二羥基丁烷對經由硝基氯硝化的去氧核醣核苷酸的反應61
2-5-11. 血紅素或血晶質與反式-2,3-二羥基-1,4-二硫基丁烷對經由過氧化亞硝酸根硝化的去氧核醣核苷酸的反應 62
2-5-12. 8-胺基鳥糞嘌呤在去氧核醣核苷酸上的半生期 63
2-5-13. 去氧核醣核苷酸上的8-硝基鳥糞嘌呤與還原時間的關係 63
第三章 實驗結果與討論 65
3-1. 雙硫醇試劑 65
3-2. 麩胺基硫 67
3-3. 還原態硫辛酸 68
3-4. 抗壞血酸 68
3-5. 酚類化合物 69
3-6. 其他的抗氧化劑 69
3-7. 還原效率 69
3-8. 控制組 69
3-9. 血紅素濃度的影響 70
3-10. 無氧條件下的還原效果 70
3-11. 還原DNA上的8-硝基鳥糞嘌呤和8-硝基黃嘌呤 71
3-12. 血紅素的蛋白質對還原硝基DNA的影響 72
3-13. 8-胺基鳥糞嘌呤在DNA上的穩定性 73
3-14. 還原硝基DNA的速度 74
3-15. 討論 75
第四章 結論 79
第五章 參考文獻 80
附圖 91

第三部分 以液相層析電噴灑游離質譜法分析細胞色素c之選擇性硝化與氧化修飾 97

英文摘要 98
中文摘要 100
第一章 緒論 101
第二章 實驗流程 107
2-1. 藥品 107
2-2. 儀器 107
2-3. 材料 108
2-4. 液相層析電噴灑游離串聯質譜儀分析系統 108
2-4-1. 液相層析儀系統條件 108
2-4-2. 質譜儀全質譜掃瞄模式條件 108
2-4-3. 質譜儀子離子掃瞄模式條件 108
2-4-4. 質譜儀選擇離子追蹤模式條件 109
2-4-5. 電噴灑游離四極柱串聯直線式離子阱質譜儀分析系統 109
2-5. 實驗步驟 109
2-5-1 過氧化亞硝酸根的合成及濃度測定 109
2-5-2. 過氧化亞硝酸根硝化細胞色素c 110
2-5-3. 細胞色素c的自硝化反應 110
2-5-4. 硝基細胞色素c的還原反應 110
2-5-5. 胰蛋白酶消化反應 110
2-5-6. 利用液相層析電噴灑游離串聯質譜儀對經胰蛋白酶消化過的細胞色素c、硝基細胞色素c以及胺基細胞色素c的定性分析 111
2-5-7. 利用液相層析電噴灑游離串聯質譜儀量測細胞色素c特定硝化位置的胜肽和參考胜肽 111
2-5-8. 利用液相層析電噴灑游離串聯質譜儀量測細胞色素c特定甲硫胺酸氧化位置的胜肽和參考胜肽 112
第三章 實驗結果與討論 113
3-1. 液相層析電噴灑游離串聯質譜儀分析經胰蛋白酶消化過的細胞色素c和硝基細胞色素c 113
3-2. 低亞硫酸鈉還原硝基細胞色素c 115
3-3. 原始參考胜肽定量法與過氧化亞硝酸根對細胞色素c的硝化選擇性 116
3-4. 過氧化亞硝酸根對細胞色素c的氧化反應 119
3-5. 細胞色素c的自硝化反應的選擇性 120
3-6. 絕對定量 122
第四章 結論 124
第五章 參考文獻 125
附圖 133
中英對照表 147

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第三部分

1.Ohshima, H.; Bartsch, H. Chronic inflection and inflammatory processed as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mut. Res. 305: 253-264; 1994.
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