臺灣博碩士論文加值系統

The objective of this research is to develop a biochemical assay using protein adducts as biomarker of environmental exposure to polycyclic aromatic hydrocarbons (PAHs) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). This methodology ultilizes trifluoroacetic acid (TFAA) and methanesulfonic acid (MSA) as catalysts to cleave cysteinyl adducts of naphthalene- and estrogen -derived quinones on proteins. The cleaved adducts are recovered by organic solvent extractions and analyzed by gas chromatography- negative-ion- chemical -ionization-mass spectrometer (GC-NICI-MS). The isomeric forms of cysteinyl adducts of naphthoquinones, including 1,2-naphthoquinone (1,2-NPQ) and 1,4-naphthoquinone (1,4-NPQ) as well as estrogen quinones, including estrogen-2,3-quinones (2-OHE2) and estrogen-3,4-quinones (4-OHE2), are characterized by using a modified procedure after adducts cleavage by the TFAA/MSA. Additionally, we refined the original protocol to purify synthetic cysteinyl adducts of estrogen and naphthalene quinones by HPLC-UV and were used as standards to quantify the modified proteins. The first part of this study was to refine the modified MT assay to analyze background level of naphthalene quinine-derived in human serum albumin and to measure the cysteinlyl adducts of naphthalene quinones in cellular proteins derived from human breast cancer cells (MCF-7) exposed to naphthalene-derived quinonoids. The second part of this study was to apply the modified MT assay to analyze the background levels of estrogen quinine-derived in human serum albumin. The third part of this study was to to develop a method for the simultaneous analysis of naphthalene and estrogen quinone-derived protein adducts in human serum albumin. Overall, we conclude that the methodology developed in this study may be applied to epidemiological study to serve as biomarkers of environmental exposure to PAHs and modulators of estrogen homeostasis.

摘 要…………………………………………………………………… I
Abstract……………………………………………………………… II
縮寫表 (List of Abbreviation) ………………………………… IV
目 錄………………………………………………………………… VI
表目錄……………………………………………………………………X
圖目錄…………………………………………………………………XII
第一章 前言………………………………………………………… 1
1-1研究緣起…………………………………………………………… 1
1-2研究目的…………………………………………………………… 1
第二章 文獻回顧……………………………………………………… 3
2-1多環芳香族碳氫化合物…………………………………………… 3
2-1-1何謂多環芳香族碳氫化合物及其環境流布…………………… 3
2-1-2 PAHs於哺乳動物細胞中之代謝機制及毒性………………… 6
2-2萘…………………………………………………………………… 9
2-2-1萘之物化特性及環境流布……………………………………… 9
2-2-2萘於哺乳動物細胞中之代謝機制………………………………12
2-2-3萘之毒性效應……………………………………………………15
2-2-4萘之代謝物及胼合物……………………………………………16
2-2-5萘作為評估多環芳香族碳氫化合物暴露之指標………………20
2-3戴奧辛………………………………………………………………22
2-3-1戴奧辛之特性及環境流布………………………………………22
2-3-2戴奧辛對人體之毒性效應………………………………………25
2-3-3戴奧辛之致癌機制………………………………………………28
2-4雌性激素……………………………………………………………32
2-4-1雌性激素之特性及環境流布……………………………………32
2-4-2雌性激素之代謝機制……………………………………………37
2-4-3雌性激素對人體之毒性及健康效應……………………………42
2-5蛋白質腁合物(Protein adducts) ………………………………44
2-5-1蛋白質腁合物作為環境暴露之生物指標………………………44
2-5-2 Protein adducts作為DNA adducts 之替代生物指標………46
第三章 實驗材料及方法……………………………………………47
3-1實驗材料……………………………………………………………47
3-1-1化學藥品及耗材…………………………………………………47
3-1-2實驗設備…………………………………………………………48
3-2實驗方法……………………………………………………………49
3-2-1 2/4-OHE-N-acetyl-L-Cysteine Adducts之製備……………50
3-2-2 E1/E2-N-acetyl-L-Cysteine Adducts製備…………………51
3-2-3 E1/E2-BSA Adducts製備………………………………………52
3-2-4 17β-Estradiol-2, 4, 16, 16, 17-d5製備其醌類代謝物及與BSA之合成 ………………………………………………………………52
3-2-5 1,2-NPQ-NAC adduct 之製備…………………………………53
3-2-6 1,2-NPQ-BSA adduct 之製備…………………………………53
3-2-7 1,4-NPQ-NAC adduct 之製備…………………………………54
3-2-8 1,4-NPQ-BSA adduct 之製備…………………………………54
3-2-9 萘同位素內部標準品之製備………………………………… 54
3-2-10 TFAA derivatization分析方法…………………………… 55
3-3 氣相層析質譜儀分析條件 ………………………………………56
3-4 HPLC純化E2-NAC Adducts之條件……………………………… 57
3-5雌性激素於人體乳癌細胞內之代謝活化與腁合物之生成………59
3-6人類血清白蛋白透析………………………………………………60
3-7透析同位素內標準品………………………………………………61
3-9 台南捐血中心捐血者之背景資料……………………………… 62
第四章實驗架構……………………………………………………… 63
4-1 實驗架構………………………………………………………… 63
4-1-1方法最佳化以冷凍乾燥取代加熱乾燥、純化蛋白、提升檢測極限及衍生產物穩定性………………………………………………… 63
4-1-2萘醌類化物與蛋白質生成之腁合物……………………………64
4-1-3以最佳化之雌性激素醌纇化物蛋白質腁合物之檢測方法檢測台南捐血中心男女生血清中之雌性激素背景值……………………… 64
4-1-4 建立能同時檢測血清中萘及雌性激素醌類化物蛋白質腁合物之檢測方法…………………………………………………………… 65
第五章 實驗結果………………………………………………………66
5-1 萘醌類化物蛋白質腁合物……………………………………… 66
5-1-1萘醌類化物與蛋白質腁合物之定性及定量……………………66
5-1-2 萘醌類化物與人類乳癌細胞MCF-7反應，檢測其蛋白質腁合物……………………………………………………………………… 75
5-2雌性激素醌類化物與蛋白質生成之腁合物………………………79
5-2-1雌性激素醌類化物與蛋白質腁合物之定性及定量……………79
5-2-2 雌性激素醌類化物蛋白質腁合物檢測方法最佳化………… 86
5-2-3台南捐血中心人類血清白蛋白(HSA)背景值之偵測………… 87
第六章 討論……………………………………………………………89
6-1 實驗及衍生方法的最佳化……………………………… ………89
6-1-1 以冷凍乾燥方式取代加熱方式…………………………… …89
6-1-2實驗中衍生方法最佳化及產物穩定性…………………………90
6-2萘醌纇化物與蛋白質生成之蛋白質腁合物………………………90
6-3台南捐血中心萘醌纇化物蛋白質腁合物與年紀之相關性………93
6-4利用改良之E2-2,3/3,4-Q蛋白質腁合物分析方法檢測台南捐血中心人類血清白蛋白中雌性激素醌類化物之背景值………………… 95
6-5 台南捐血中心人類血清白蛋白中雌性激素醌類蛋白質腁合物與年齡之相關性………………………………………………………… 97
6-6 台南捐血中心人類血清白蛋白中雌性激素醌類蛋白質腁合物與萘醌纇蛋白質腁合物之相關性……………………………………… 99
第七章 結論與建議……………………………………………… 101
7-1萘醌類化物與蛋白質生成之蛋白質腁合物…………………… 101
7-2雌性激素醌類化物與蛋白質生成之蛋白質腁合物…………… 102
7-3未來方向………………………………………………………… 103
第八章 參考文獻……………………………………………………104

第八章 參考文獻
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