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研究生:曹文卿
研究生(外文):Wen-Ching Tsao
論文名稱:一、停經後婦女服用大豆植物性荷爾蒙後對於凝血系統影響之評估二、鎳金屬抑制人類細胞核酸配對錯誤修復機制之分析
論文名稱(外文):1.Evaluation of Dietary Soy Containing Phytoestrogens on the Hemostatic System in Postmenopausal Women 2.Analysis of Nickel Inhibiting Human MutSβMismatch Repair Pathway
指導教授:方偉宏方偉宏引用關係
指導教授(外文):Woei-Horng Fang
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2008
畢業學年度:97
語文別:中文
論文頁數:65
中文關鍵詞:植物性荷爾蒙停經鎳金屬人類細胞核酸配對錯誤修復
外文關鍵詞:PhytoestrogensPostmenopausalNickelHuman Mismatch repair
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婦女停經後常有生理上的不適稱為停經症候群,如何減輕停經症候群造成的不適是很受重視的。臨床上針對停經症候群嚴重的婦女是給予類固醇荷爾蒙治療,以減輕停經症候群造成的不適,然而也陸續有研究發現這種療法有種種副作用,包括深部靜脈血栓、心血管疾病發生率增加、乳癌、陰道異常出血及子宮內膜癌等疾病的發生。因此如何能達到荷爾蒙治療效果並避免副作用的發生是最引人興趣的課題。近幾年,自植物中萃取出類似雌激素的成分(稱為植物性荷爾蒙),其具有雌激素減緩停經症候群的作用,然而這種藥物是否會產生雌激素的副作用則尚未證實,因此本研究是要探討停經婦女在服用大豆植物性荷爾蒙後,與靜脈血栓相關的凝血因子是否會產生變化。

本研究受試者是來自於台大醫院參與骨質疏鬆防治計畫中的100名自願受試者,這些受試者無明顯停經症候群,也未進行荷爾蒙替代療法,隨機將受試者分成實驗組及對照組,分別給予服用大豆植物性荷爾蒙或安慰劑,進行雙盲實驗,並分別於服用前、服用後6個月、服用後12個月各抽一次血進行凝血因子分析。分析項目共五項:Factor VII、D-dimer、vWF Ag、Protein S、PAI-1。

利用t檢定 (t test)分析後發現服用大豆植物性荷爾蒙或服用安慰劑的受試者之血中凝血因子的變化並無顯著的差異性,也就是說,服用大豆植物性荷爾蒙並不會影響血中凝血因子的變化。


核酸配對錯誤修復系統可以修復核酸複製時的錯誤以維護基因體的穩定,缺乏這個修復系統會造成遺傳不穩定進而可能引發癌症。IARC (Internal Agency for Research on Cancer) 已將重金屬鎳認定為人類第一型致癌物質,若長期暴露在含鎳的環境下會增加罹患肺癌和鼻咽癌的機會。

二價鎳離子是常見的環境及工業染污物,而且已知與肺癌的產生有關。以二價鎳離子處理人類細胞,會產生短的重覆序列核酸的縮減或延伸,也就是所謂的微衛星不穩定現象,而這也是細胞缺乏核酸配對錯誤修復能力的重要特徵。本研究的目的是為了確認鎳是否會抑制小量核酸插入或刪除的配對錯誤修復,也就是MutSβ所參與的修復活性。

本研究是利用一組含4個鹼基插入或刪除之異雙股核酸,測試鎳離子對MutSβ修復機制的影響,我們發現這4種異雙股核酸的修復皆會受到鎳離子的抑制,而且與加入鎳離子的濃度具相關性。為了解鎳作用於酵素的那一種殘基,我們分別於抑制反應中添加十六種胺基酸,結果發現天門冬醯胺酸(Asparagine)對於鎳的抑制最具保護效果。而在抑制反應中加入含硫氫基(sulfhydryl group,-SH)的dithiothreitol,發現可恢復部分的修復反應。

以上結果證實鎳離子會抑制人類MutSβ鹼基配對錯誤修復系統,而此種抑制效果將會造成基因的不穩定性,成為引發癌症的發生的重要機制之一。
Menopause is the cessation of a woman''s menstrual periods and usually occurs between ages 45 and 55. During menopause many women experience such symptoms as hot flashes, depression, anxiety, insomnia, fatigue, heart palpitations, and weight gain. Post menopausal hormone replacement therapy (HRT) could reduce menopausal syndrome. Physicians routinely prescribed estrogens for women who complained of hot flashes and other symptoms associated with menopause. Unfortunately, this medical practice greatly increased the chances for developing cancer, thrombophlebitis, strokes and heart attacks in many women. Recently, physicians are now aware of this danger and seeking safer and effective substitutes such as phytoestrogens in treating menopausal symptoms. However, it is not understood whether phytoestrogens may cause similar side effects as estrogen treatment. The purpose of this study is to evaluate thrombophlebitis related coagulation factors after phtoestrogens treatment.
The subjects were volunteers from Osteoporosis Prevention Plan of National Taiwan University Hospital. One hundred healthy postmenopausal women without menopausal symptoms and hormone replacement therapy were enrolled in a randomized double-blind trial conducted over 12 months. The phtoestrogen used in this study was isoflavone. The blood were sampled before treatment, after 6 months and in the end of 12 months. Thrombophlebitis related coagulation factors of Factor VII, D-dimer, vWF Ag, Protein S, PAI-1 were analyzed in this study. Using Student''s t tests analysis, we found there were no significant differences of all five coagulation factors between the groups taking the placebo and isoflavone. Therefore, treatment of isoflavone did not show adverse effect to coagulation factors tested.


Mismatch repair (MMR) maintains genome stability by correction of DNA biosynthetic errors during the replication. Inactivation of MMR activity results in genetic instability, which is assumed to promote tumorigenesis.
Nickel (II) is a ubiquitous environmental and industrial contaminant. It is also a well-known human carcinogen causing respiratory cancers. Human cells treated with Ni(II) had been shown microsatellite instability of short tandem repeat contraction and expansion, a well-known signature of losing mismatch repair capability. The purpose of this study was to determine whether Nickel (II) may cause genetic instability by inhibiting human mismatch repair, specifically small nucleotide insertion/deletion repair related MutSβ pathway.
We used a set of 4-nucleotide insertion/deletion heteroduplexes to examine the effect of nickel (II) on MutSβ mismatch repair pathway in human cells. We found that addition of nickel (II) significantly inhibits human mismatch repair and the inhibition appears to be dose dependent. However, the inhibition of mismatch repair is prevented by asparagine, suggesting that these residues are essential for the repair enzymes and are targeted by nickel (II). Using sulfhydryl containing chemicals, we have found that the inhibitory effect of Nickel (II) on the mismatch repair activity was overcome by addition of dithiothreitol but not β-mercaptoethanol. Our results provide strong evidence that nickel (II) can inhibit mismatch repair pathway in human cells, and this may constitute one of the important mechanisms of nickel (II)-induced human carcinogenesis.
Part.1
總目次 II
圖目次 III

表目次 IV

中文摘要 2
英文摘要 3
縮寫表 4
前言 5
材料與方法 9
一、受試者檢體來源與實驗設計 9
二、受試者檢體之採集、分離與保存 10
三、檢驗試劑之成分與原理 10
四、檢驗試劑之品管操作 14
五、凝血系統因子結果之分析工具 14
結果 15
討論 16
附圖 18
附表 20
參考文獻 22

圖目次
圖一、動物性雌激素(Estrogen)與植物性雌激素(Phytoestrogen)的結構比較圖 18
圖二、服用大豆植物性荷爾蒙或安慰劑後結果比較圖 19

表目次
表一、服用大豆植物性荷爾蒙組或安慰劑組之基本資料比較表 20
表二、服用大豆植物性荷爾蒙或安慰劑後P value比較表 21

Part.2
總目次 V

圖目次 VII

表目次 VIII

中文摘要 28
英文摘要 29
縮寫表 30
前言 31
材料與方法 34
一、菌株 34
二、人類細胞株之繼代培養 34
三、人類細胞核萃取液之製備 35
四、鎳離子 36
五、突變噬菌體M13mp18 mutant之建構 36
六、M13mp18系列雙股核酸之製備 37
七、M13mp18系列單股核酸之製備 38
八、具斷股異雙股核酸之建構 39
九、異雙股核酸對測定用限制酵素之敏感度分析 41
十、試管中修復反應(In vitro Repair Assay) 41
十一、鎳對異雙股核酸的抑制反應 42
十二、硫氫化合物還原劑對鎳抑制的影響 43
十三、胺基酸對鎳抑制的影響 44
結果 45
討論 50
附圖 53
附表 62
參考文獻 63

圖目次
圖一、含四個鹼基插入之異雙股核酸(3''C4)示意圖 53
圖二、3''C4之限制酵素分析試管內修復情形之示意圖 54
圖三、人類細胞鹼基配對錯誤修復系統 55
圖四、鎳對鹼基配對錯誤修復系統修復3''C4效率之分析 56
圖五、鎳對鹼基配對錯誤修復系統修復5''C4效率之分析 57
圖六、鎳對鹼基配對錯誤修復系統修復3''V4效率之分析 58
圖七、鎳對鹼基配對錯誤修復系統修復5''V4效率之分析 59
圖八、還原劑對鎳抑制鹼基配對錯誤修復反應之分析 60
圖九、胺基酸對鎳抑制鹼基配對錯誤修復反應之影響 61

表目次
表一、異雙股核酸之命名、來源及個別分析用辨識酵素 63
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