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研究生:陳清俊
研究生(外文):Ching-Jiunn Chen
論文名稱:內生性脂質過氧化抑制因子的功能角色
論文名稱(外文):Functional role of an endogenous inhibitor of lipid peroxidation
指導教授:張文昌張文昌引用關係
指導教授(外文):Wen-Chang Chang
學位類別:博士
校院名稱:國立成功大學
系所名稱:基礎醫學研究所
學門:醫藥衛生學門
學類:醫學學類
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:158
中文關鍵詞:麩胺基硫脂氧酵素磷脂過氧化物麩胺基硫過氧化酵素人類上皮癌細胞
外文關鍵詞:A431 cellsGSHlipoxygenasePHGPx
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  • 被引用被引用:2
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中 文 摘 要

氧自由基在細胞內累積過量,將會導致細胞功能的異常,並引發整個器官的病變,其中包括血管、腦、以及腎臟等等。至於細胞內氧自由基的來源,部份是來自於一些可代謝不飽合脂肪酸的酵素反應,此類酵素統稱為脂氧酵素,其中包含脂氧酵素、環氧酵素、以及單氧酵素等等。一旦這些酵素在細胞內的調控失常,或是經其代謝而得之含氧自由基產物無法迅速地被下游酵素所代謝時,則易造成氧自由基分子在胞內過度的累積,而直接威脅到細胞的正常運作。因此研究細胞如何去調控這些脂氧酵素的表現,以降低氧自由基分子對細胞可能帶來的傷害,便成為此篇論文之主要研究目的。
本實驗室先前在人類上皮癌細胞A431中,發現在其細胞溶質(cytosol)裡含有一種可在in vitro狀態下,抑制十二脂氧酵素代謝花生四烯酸的因子存在。此抑制因子經由一系列的酵素特性分析、蛋白質純化、胺基酸序列比對、以及獨特的酵素活性測試後,證實其為磷脂過氧化物麩胺基硫過氧化酵素(PHGPx)。利用試劑去除細胞內PHGPx的輔因子麩胺基硫(GSH),可促使胞內脂氧酵素代謝花生四烯酸的產物明顯地增加,其中以環氧酵素的代謝產物尤為明顯。就抑制十二脂氧酵素的活性而言,同樣也是存在於A431細胞中的麩胺基硫過氧化酵素1 (GPx 1),其對GSH的需求性較PHGPx為低,因此藉由降低細胞內GSH的量而導致脂氧酵素活性上升的主因,極可能是直接影響到PHGPx的活性表現所致。此外,在人類血小板的細胞溶質中,缺乏PHGPx之酵素活性表現,可能是其十二脂氧酵素得以表現的最大因素。至此初步論定PHGPx可能是細胞內脂氧反應的主要調控者。在調控脂氧酵素活性的機制方面,由於多項證據顯示,脂氧酵素及環氧酵素的初始反應是需要少量的氫過氧化因子(hydroperoxides)來參與其運作,因此PHGPx在A431細胞裡可能便透過其可代謝hydroperoxides的機制,而間接地影響到脂氧酵素的活性表現。此機制的表現,可由細胞外給13-HPODE會促使胞內脂氧酵素代謝花生四烯酸的產物增加而加以證實。為了更進一步證明細胞內PHGPx參與脂氧酵素之調控,我們構築了幾種質體,並利用他們將A431細胞轉形為穩定型之細胞株。之中可大量表現含標籤的PHGPx之A431細胞株,其胞內含標籤之PHGPx可被Xpress抗體以及PHGPx抗體所認得,經PHGPx典型酵素活性測試後,證實它也具備有PHGPx之酵素活性。以此細胞株來做完整細胞之分析,發現它代謝花生四烯酸的產量明顯較控制組為低,證實PHGPx大量表現果然可直接抑制脂氧酵素之活性。另一方面,短效性送入一段可抑制PHGPx生合成之寡核酸(oligonucleotide),可造成該細胞代謝花生四烯酸的產量明顯地上昇。此外,利用可大量表現抗PHGPx 之訊息核醣核酸(mRNA)的A431穩定型細胞株去做完整的細胞分析,結果發現它代謝花生四烯酸的產量較控制組明顯地提高許多,證實了當PHGPx被移除時果然會導致脂氧酵素的活性增加,至此我們下了一個結論,那就是PHGPx在細胞內是具有調控脂氧酵素反應之功能。
英 文 摘 要

The accumulation of oxygen radicals injures the functions of cells and leads to the pathogenesis of some organs including vascular, brain, and kidney and so on. Important sources of the oxygen radicals are reactions associated with the metabolism of unsaturated fatty acids, such as lipoxygenases, cyclooxygenases (COXs), and monooxygenases. If the regulation of these enzymes is abnormal, or the downstream degradation enzymes lose their catalysis, it will result in the accumulation of oxygen radicals and affect the normal functions of the cells. Therefore, to study how cells regulate the expression of these enzymes and maintain cells away from the damage of oxygen radicals was the main aim of this study.
In our preliminary studies, we found that a factor in the cytosolic fraction of human epidermoid carcinoma A431 cells could inhibit the activity of arachidonate 12-lipoxygenase (12-LOX) in vitro. After serial studies on its purification, characterization, analysis of amino acid sequence, and specific activity, we identified that the inhibitor as phospholipid hydroperoxide glutathione peroxidase (PHGPx). Depletion of glutathione (GSH) in cells resulted in up-regulation of the enzyme activities of COX and 12-LOX, especially on COX. In terms of the inhibitory effect on 12-LOX activity, PHGPx was more sensitive to GSH concentrations than glutathione peroxidase 1, suggesting that treatment of cells with GSH depleting agents would essentially abolish the enzyme activity of PHGPx. Additionally, the high activity of 12-LOX in the cytosolic fraction of human platelet might due to the lack of PHGPx activity. It appears that PHGPx is a major regulator of lipid oxygenation in A431 cells. The accumulated evidence indicates that hydroperoxide plays an important role in the initial reaction of these oxygenases, and that the PHGPx may inhibit the start reaction of these enzymes by removing hydroperoxides. The lipid oxygenation stimulated by 13-hydroperoxyoctadecadienoic acid in GSH-depleted cells supported this notion. To get more direct evidence of this hypothesis, we constructed a serial of plasmids and transformed into A431 cells. A stable transfectant overexpressing tag-PHGPx which could be recognized by either Xpress or PHGPx antibodies and contains the specific enzyme activity of PHGPx was established. The metabolism of arachidonic acid by COX and 12-LOX significantly decreased in stable transfectants overexpressing PHGPx compared to that in a vector-control cell line, suggesting that overexpressing PHGPx in cells could inhibit the lipid oxygenation. In addition, inhibition of PHGPx activity by the treatment of cells with antisense oligonucleotide of PHGPx mRNA increased the enzymatic catalysis of both COX and 12-LOX. The metabolism of arachidonic acid by COX and 12-LOX significantly increased in stable transfectants overexpressing antisense of PHGPx mRNA compared to that in a vector-control cell line, suggesting that blocking the biosynthesis of PHGPx by antisense of PHGPx mRNA would up-regulate lipid oxygenation in cells. Consequently, we conclude that PHGPx can regulate the enzyme activity of oxygenases in A431 cells.
目 錄


考試合格證明 Ⅰ
中文摘要 Ⅱ
英文摘要 Ⅳ
誌 謝 Ⅵ
表 目 錄 Ⅹ
圖 目 錄 ⅩⅠ
檢 索 表 ⅩⅣ


第一章 緒 論 1
第一節 引言 1
第二節 本論文之研究概要 4

第二章 實驗材料及實驗方法 18
第一節 實驗材料 18
第二節 溶液與試劑之配製 25
1. 抑制因子之特性探討 25
2. 抑制因子之純化 26
3. 蛋白質濃度之測定 27
4. 細胞溶解液之配置 28
5. 電泳以及西方點墨法 28
6. 硝酸銀染色法 31
7. 完整細胞之花生四烯酸代謝分析 31
8. GPx酵素活性測試 32
9. PHGPx酵素活性測試 34
10. GSH分析 35
11. RNA之抽取以及北方點墨法 36
12. 質體之構築以及製備 38
第三節 實驗方法 39
A. 細胞培養 40
B. 微粒體(microsomes)和細胞溶質(cytosol)的製備 40
C. 細胞溶解液(lysate)的製備 41
D. 十二脂氧酵素(12-LOX)之酵素活性測定 41
E. 過氧化抑制因子的活性測定 41
F. 環氧酵素(COX)之酵素活性測定 42
G. 蛋白質濃度的測定 42
H. 過氧化抑制因子之純化 43
I. 電泳(SDS-PAGE)以及西方點墨法(Western blot) 49
J. GSH之測定 51
K. PHGPx的酵素活性測定 51
L. GPx的酵素活性測定 52
M. 完整細胞之脂氧酵素代謝花生四烯酸的測定 52
N. 北方吸墨法(Northern blot) 53
O. Antisense oligonucleotide之轉殖(transfection) 54
P. 質體之構築 55
Q. DNA轉殖與篩選穩定型細胞株 59
R. Virion之感染細胞與篩選穩定型細胞株 61

第三章 實驗結果與討論 62
第一節 抑制因子之純化以及證實他是phospholipid hydroperoxide
glutathione peroxidase (PHGPx) 62
1. 引言 62
2. 結果與討論 64

第二節 利用藥物來分析PHGPx抑制脂氧酵素活性的原理,並證明
其在A431細胞中之功能與角色 75
1. 引言 75
2. 結果與討論 76

第三節 利用可大量表現PHGPx的細胞株,來探討PHGPx在細胞
內之功能 89
1. 引言 89
2. 結果與討論 91

第四節 利用anti-PHGPx mRNA之oligonucleotide或不表現PHGPx
的細胞株,來證實PHGPx的確可在細胞內調控脂氧酵素的活性 105
1. 引言 105
2. 結果與討論 106

第四章 總 論 124

參考文獻 132
已發表之文獻著作 143
附錄 144
自述 158
參 考 文 獻


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