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研究生:吳勝雄
研究生(外文):Sheng-hsiung Wu
論文名稱:蛋白質胼合物作為生物指標評估雌性激素類化物組織劑量之研究
論文名稱(外文):Applications of Protein Adducts as Biomarkers to Investigate the Dosimetry of Estrogen Quinonoids
指導教授:林伯雄林伯雄引用關係
指導教授(外文):Po-hsiung Lin
學位類別:碩士
校院名稱:國立中興大學
系所名稱:環境工程學系
學門:工程學門
學類:環境工程學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:75
中文關鍵詞:蛋白質胼合物alkaline permethylation雌性激素雌性激素類化物氣相層析質譜儀甲基碘
外文關鍵詞:protein adducts鹼性烷化estrogenestrogen quinoneGC/EIMSCH3I
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本研究係以發展一生物指標分析法,針對雌性激素類化物與蛋白質形成之共價鍵結產物-胼合物(protein adduct),作為推估雌性激素類化物於標的器官之組織劑量,進行一系列之探討。運用鹼性烷化分析法(alkaline permethylation),以甲基碘為衍生劑,並以氫氧化鈉為催化劑,將雌性激素之類化物與蛋白質中氨基酸-cysteine硫原子所生成之併合物自蛋白質結構移除,經由有機溶劑萃取與濃縮,進行氣相層析電子撞擊式質譜儀(GC/EIMS)分析。本研究已成功地建立此一分析法,並完成對雌性激素類化物包括estrogen-2,3-quinone及estrogen-3,4-quinone與cysteine、glutathione、及蛋白質形成之胼合物之定性分析。同時針此一分析方法進行反應條件之最佳化測試,並推估鹼性烷化之偵測極限在250 pmole至1 nmole之間。此外,運用高效能液相層析儀純化雌性激素之類化物之cysteine胼合物,作為定量所需檢量線之標準品。並針對bovine serum al-bumin於生理條件下與estrone-3,4-quinone反應後,經運用鹼性烷化分析法推估其estrone-3,4-quinone-BSA adducts生成量與添加之estrone-3,4-quinone濃度相關性約為2.92 nmole/g protein/nM,而鹼性烷化分析法可偵測至最低曝露濃度為10 nM。針對以estrone-3,4-quinone於相同曝露濃度(10 mM)與時間下於人類乳癌細胞T-47D反應,鹼性烷化分析法未偵測到E1-3,4-Quinone所生成protein adduct。
The objective of this research is to develop a biochemical assay using protein adducts as biomarker of exposure to assess the cumulative body burden of estrogen quinones in target organs. The alkaline permethyla-tion procedure which used methyl iodine and sodium hydroxide as cata-lysts to cleave cysteinyl adducts of estrogen quinones. The cleaved ad-ducts are recovered by organic solvent extractions and analyzed by gas chromatography/electron-impacted mass spectrometer (GC-EIMS). Cysteinyl adducts of estrogen-2,3- quinone and estrogen-3,4-quinone on cyteines (Cys), glutathiones (GSH) and bovine serum albumins (BSA) are characterized by the alkaline permethylation procedure. Results from the optimization of the alkaline permethylation procedure reveal that the optimal condition for adduct cleavage is when modified cysteines react with 6N NaOH and 1 mL of CH3I at 100℃ for 6 hours. The limit of detection is estimated to be between 250 pmole and 1 nmole on column. Additionally, the synthetic cysteinyl adduct of estrogen-3,4-quinone was further purified by HPLC-UV and was used to quantify modified proteins. Regression analysis of the concentration-adduct levels of indicates that the production of E1-3,4-quinone-modified BSA adducts was estimated to be 2.92 nmole/g protein/nM.
第一章 前言 1
第二章 文獻回顧 2
2-1雌性激素致癌風險 2
2-2雌性激素之代謝及致癌機制 5
2-2-1 雌性激素之代謝 5
2-2-2 影響雌性激素代謝之因子 11
2-2-3 雌性激素之致癌機制 12
2-2-3-1 受體鍵結之致癌模式 12
2-2-3-2 基因毒性之致癌模式(Genotoxicity-mediated carcinogenesis model) 12
2-3雌性激素干擾物質之作用機制 15
2-4 以蛋白質胼合物(Protein Adduct)作為生物指標(biomarker) 16
2-4-1 生物指標定義及分類 16
2-4-2 雌性激素的生物指標研究 18
2-5 蛋白質胼合物(Protein Adduct)之動力學 20
第三章 實驗材料與方法 25
3-1實驗材料 25
3-2 Estrogen quinone之 cysteine/glutathione adduct之合成 26
3-2-1 4-OHE2-2-cysteine adduct 製備 27
3-2-2 4-OHE2-2-glutathione adduct製備 27
3-2-3 4-OHE2-BSA adduct 製備 27
3-2-4 2-OHE2- cysteine adduct 製備 28
3-2-5 4-OHE1-2-cysteine adduct 製備 28
3-2-6 4-OHE1-2-glutathione adduct 製備 29
3-2-7 4-OHE1-BSA adduct 製備 29
3-3 鹼性烷化分析法(Alkaline Permethylation) 30
3-3-1 氣相層析質譜儀(Gas chromatography / Mass spectrometer -electron impact)分析條件 32
3-3-2 以HPLC純化4-OHE1-2-cysteine adducts條件 32
3-3-3 鹼性烷化條件之最佳化 33
3-4 由雌性激素製備其類代謝物 34
3-5鹼性烷化偵測之運用 35
3-5-1 人類乳癌細胞株 35
3-5-2 人類白蛋白(albumin)背景adduct測試 35
第四章 實驗結果與討論 37
4-1 雌性激素類衍生物與cysteine, GSH, 及protein 生成adduct之定性質譜圖 37
4-1-1 4-OHE1 Thioether Adduct 37
4-OHE1-cysteine adduct 37
4-OHE1-2-Glutathione (GSH) adduct 39
4-OHE1-BSA adduct 40
4-1-2 4-OHE2 Thioether Adduct 42
4-OHE2-2-cysteine adduct 42
4-OHE2-2-glutathione adduct 44
4-OHE2-BSA adduct 45
4-1-3 2-OHE2-cysteine adduct 47
4-1-4 運用fremy’s salt氧化雌性激素直接製備E1-2,3-Q與 E1-3,4-Q之cysteine adduct 49
4-1-5 運用fremy’s salt氧化雌性激素直接製備E2-2,3-Q與 E2-3,4-Q之cysteine adduct 51
4-2 HPLC純化標準品與檢量線製作 53
4-3 E1-3,4-Quinone與BSA之劑量-效應關係 55
4-4 鹼性烷化反應條件之探討 56
4-4-1 反應時間與溫度之影響 56
4-4-2 氫氧化鈉當量濃度之影響 57
4-4-3 甲基碘用量之影響 58
4-5 鹼性烷化於人類白蛋白與細胞蛋白質之偵測 59
第五章 結論與未來工作 65
5-1 結論 65
5-2 未來工作 66
參考文獻 69
參考文獻
行政院衛生署89年臺灣地區主要死因分析
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