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研究生:黃淑美
研究生(外文):Shu-Mei Huang
論文名稱:同半胱胺酸硫化內酯誘發哺乳動物細胞傷害及相關營養素對細胞傷害調節之探討
論文名稱(外文):Modulation of Antioxidants and Folate Related-Nutrients on Homocysteine Thiolactone Induced-Apoptosis in Mammalian Cell Lines
指導教授:許瑞芬許瑞芬引用關係
指導教授(外文):Rwei-Fen S. Huang
學位類別:碩士
校院名稱:輔仁大學
系所名稱:食品營養學系
學門:醫藥衛生學門
學類:營養學類
論文種類:學術論文
論文出版年:2000
畢業學年度:88
語文別:中文
論文頁數:103
中文關鍵詞:同半胱胺酸硫化內酯細胞凋亡過氧化氫caspase-3CHOHL-60
外文關鍵詞:homocysteine thiolactoneapoptosisH2O2caspase-3CHOHL-60
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輔仁大學八十八學年度第二學期碩士論文摘要
系(所)別:食品營養學系 研究生:黃淑美
論文名稱:同半胱胺酸硫化內酯誘發哺乳動物細胞傷害及相關營養素對細胞傷害調節之探討
指導教授:許瑞芬 博士
摘 要
同半胱胺酸對血液循環系統之細胞傷害機制已有詳細的研究,但對於其它局部組織細胞之影響則未知。本研究發現病理濃度的同半胱胺酸衍生物(同半胱胺酸硫化內酯) 會誘發人類前骨髓血癌HL-60細胞程式凋亡。同半胱胺酸硫化內酯誘發HL-60之程式凋亡,造成磷脂絲胺酸露出細胞表面的比例增加、具有低染色體套數DNA的細胞增加,及細胞核內DNA呈現180~200鹼基對大小的斷裂形式。同半胱胺酸硫化內酯對細胞膜及核DNA造成的程式凋亡,隨著劑量及處理時間的增加而增加。同半胱胺酸硫化內酯促使細胞內活性氧化物種H2O2於凋亡特徵出現前增加了2~6倍,隨即活化程式凋亡執行蛋白caspase-3的活性。Caspase-9抑制劑延遲同半胱胺酸硫化內酯引發的caspase-3活化,但無法完全抑制凋亡的發生。過氧化氫可完全清除HL-60細胞內的H2O2,抑制caspase-3的活化,防止同半胱胺酸硫化內酯處理導致DNA受損及細胞膜破壞的發生,但超氧化物歧化則無明顯效果。抗氧化營養素NAC、Vit. C可部分抑制同半胱胺酸硫化內酯誘發的H2O2生成、caspase-3活化和凋亡,Vit. E可減少低染色體套數DNA的比例,但外加同半胱胺酸相關營養素(葉酸、維生素B6和B12)則沒有明顯抑制效果。同半胱胺酸硫化內酯對中國大頰鼠卵巢細胞(CHO)只有產生遲滯生長的現象,而且對葉酸代謝不同的CHO之毒性程度不同,以粒線體葉酸代謝異常的GlyA反應最明顯。由這些結果可知,不同類型細胞對同半胱胺酸硫化內酯的細胞染色體傷害毒性之敏感度不同。同半胱胺酸硫化內酯可能是藉由產生過氧化氫,經caspase-9途徑而引起caspase-3活化,進而誘發HL-60細胞凋亡。營養素中以NAC、Vit. C和Vit. E對同半胱胺酸硫化內酯誘發的凋亡有較佳的抑制作用。外加葉酸、維生素B6和B12沒有作用,但細胞內葉酸的代謝可調節同半胱胺酸硫化內酯的毒性。
關鍵字:同半胱胺酸硫化內酯、細胞凋亡、過氧化氫、caspase-3、CHO、HL-60
Modulation of Antioxidants and Folate Related Nutrients on Homocysteine Thiolactone Induced Apoptosis in Mammalian Cell Lines
Shu-Mei Huang
Abstract
The cytotoxicity of homocysteine on localized tissues other than from circulatory system is not well established. The present study revealed that human promyeloid leukemia HL-60 cells were induced apoptosis by homocysteine derivatives (HcyT) treatment at pathological concentrations. Apoptosis induced by HcyT was characterized by increased phosphatidylserine (PS) exposure on the cell membrane surface, increased apoptotic cells with hypoploid DNA contents, and internucleosomal DNA fragmentation, all of which occurred in a time- and dose-dependent manner. HcyT treatment also significantly increased intracellular reactive oxygen species H2O2 and caspase-3 activity, which was accompanied by the appearance of apoptotic features. Addition of caspase-9 inhibitor to HcyT-treated HL-60 cells delayed caspase-3 activation, but could not completely prevent cells from apoptotic damage. Preincubation of HcyT-treated HL-60 cells with catalase completely scavenged intracellular H2O2, thus inhibiting caspase-3 activity and protecting cells from apoptotic DNA damage and membrane injury. Conversely, antioxidants of NAC, Vit C and Vit E partially inhibited HcyT-induced H2O2 production、caspase-3 activation and apoptosis. Neither SOD nor Hcy- metabolizing nutrients (folate, vitamin B6 and B12) had the significant effects on the prevention of HcyT-treated HL-60 cells from apoptotic damage. Chinese hamster ovary cells (CHO) were less sensitive to HcyT-induced cytotoxicity than HL-60 cells. Cells with mitochondrial defects were more sensitive to HcyT-induced cell growth arrest than cells with cytosol defects. Taken together, these results suggest that different cell types have different susceptibility to HcyT toxicity. HcyT treatment induced apoptosis in HL-60 cells through H2O2 generation, and caspase-3 activation. Antioxidants of NAC、Vit C and Vit E could partially reduce HcyT-exerted apoptotic damage. Addition of folate、Vit B6 and B12 had no significant effects on HcyT-induced apoptotic damage, yet intercompartment folate metabolism could modulate HcyT-induced cytotoxicity.
Key words: homocysteine thiolactone、apoptosis、H2O2、caspase-3、CHO、HL-60
目 錄
頁次
中文摘要……………………………………………………………i
英文摘要……………………………………………………………iii
誌謝…………………………………………………………………v
目錄…………………………………………………………………vii
表目錄……………………………………………………………xi
圖目錄……………………………………………………………xii
縮寫表……………………………………………………………xiv
第一章 前言………………………………………………………….1
第二章 文獻回顧…………………………………………………….3
一、同半胱胺酸生化………………………………………………3
(一)同半胱胺酸之生化代謝……………………………………....3
(二)影響血同半胱胺酸的因素……………………………………4
1.遺傳性因子……………………………………………………4
2.營養性因子……………………………………………………5
3.其它相關因子…………………………………………………6
(1) 性別、雌激素和懷孕………………………………………6
(2) 生活型態……………………………………………………6
(3) 腎衰竭………………………………………………………7
(4) 移植…………………………………………………………7
二、高血同半胱胺酸對心血管系統的傷害性…………………….7
(一)高血同半胱胺酸與心血管疾病的關係………………………7
(二)高血同半胱胺酸與染色體傷害的關係………………………8
(三)同半胱胺酸可能的細胞傷害機制……………………………9
1.氧化傷害………………………………………………………9
2.蛋白質結構的損傷……………………………………………...11
3.脂蛋白硫醇化作用……………………………………………….12
三、同半胱胺酸的染色體傷害之可能機制-程式凋亡……………12
(一)細胞壞死………………………………………………………..13
(二)細胞程式凋亡…………………………………………………....13
(三)細胞程式凋亡的調控……………………………………………...14
1. Caspase家族……………………………………………….14
2. Caspase受質…………………………………..………...16
3. Caspase的調節路徑…………………………………………17
4. Caspase活性的調節…………………………………………17
(1) Bcl-2家族…………………………………………………18
(2) Ceramide…………………………………………………..18
(3) Nuclear factor-κB………………………………………….19
四、氧化壓力誘發細胞程式凋亡……………………………….19
五、同半胱胺酸硫化內酯的形成………………………………..21
六、先前研究結果……………………………………….……….23
第三章 材料與方法……………………………………………………28
一、 實驗材料…………………………………………………………..28
1. 細胞株………………………………………………………….28
2. 細胞培養材料…………………………………………………28
3. 分析用試藥……………………………………………………..28
4. 儀器設備………………………………………………………..28
二、 實驗方法…………………………………………………………..28
1. 細胞壞死及磷脂絲胺酸(PS)外露測定……………………28
2. 低染色體套數(hypoploid)細胞與蛋白質的測定…………29
3. DNA laddering斷片測定…………………………………30
4. 細胞內過氧化氫含量測定…………………………………30
5. 細胞內超氧陰離子含量測定………………………………31
6. Caspase-3活性測定…………………………………………31
7. 細胞生長抑制分析………………………………………………32
第四章 定性與定量同半胱胺酸硫化內酯誘發人類前骨髓血癌HL-60細胞的程式凋亡……………………………..…………………33
一、實驗目的及設計………………………………………………33
二、結果…………………………………………………………33
(一)定量HcyT造成HL-60細胞壞死……………………………33
(二)定量HcyT誘發HL-60程式凋亡之細胞膜傷害……………34
(三) HcyT對HL-60細胞生長週期及低染色體套數程式凋亡細胞之影響………………………………………………………….34
(四) HcyT對HL-60細胞內蛋白質相對含量之影響……………34
(五) HcyT造成HL-60細胞程式凋亡DNA斷片……………….35
(六) HcyT對HL-60細胞內過氧化氫產生之影響………………35
(七) HcyT對HL-60細胞內超氧陰離子產生之影響……………35
(八) HcyT對HL-60細胞內caspase-3活性之影響……………..36
(九) Caspase-9抑制劑及過氧化氫對HcyT活化HL-60細胞內caspase-3之影響…………………………………………….36
(十) Caspase-3抑制劑對HcyT引起HL-60細胞凋亡之影響….37
第五章 抗氧化物及葉酸、維生素B6、B12對同半胱胺酸硫化內酯誘發HL-60細胞凋亡的調節…………………..……………48
一、實驗目的及設計….…………………………………48
二、結果…………………………………………………………48
(一)添加抗氧化物對HcyT誘發HL-60程式凋亡細胞膜傷害之影響……………………………………………………………48
(二)添加葉酸、維生素B6及B12對HcyT誘發HL-60細胞程式凋亡細胞膜傷害之影響………………………………………49
(三)抗氧化物的添加對HcyT造成HL-60程式凋亡DNA傷害之調節…………………………………………………………49
(四)維生素C的添加對HcyT造成HL-60程式凋亡DNA傷害之調節………………………………………………………..…49
(五)葉酸、維生素B6及B12的添加對HcyT造成HL-60程式凋亡DNA傷害之調節……………………………………….………50
(六)抗氧化營養素及同半胱胺酸代謝營養素對HL-60細胞因HcyT誘發DNA斷片產生之影響………………………….…50
(七)抗氧化營養素對HL-60細胞內HcyT誘發過氧化氫產生之影響…………………………………………………………….50
(八)葉酸、維生素B6及B12對HL-60細胞內HcyT誘發過氧化氫產生之影響………………………………………………….50
(九)抗氧化營養素對HL-60細胞內HcyT引起超氧陰離子產生之影響………………………………………………………….50
(十)葉酸、維生素B6及B12對HL-60細胞內HcyT引起超氧陰離子產生之影響………………………………………………….51
(十一)抗氧化物的添加對HcyT引起HL-60細胞caspase-3活化之影響………………………………………………….…….51
(十二)葉酸、維生素B6及B12的添加對HcyT引起的caspase-3活化之影響…………………………………………………….51
第六章 細胞內葉酸代謝影響同半胱胺酸硫化內酯的氧化傷害性...64
一、實驗目的及設計……………………………………………….64
二、結果…………………………………………………………65
(一)添加過氧化氫對CHO細胞生存率的影響…………………65
(二)添加HcyT對CHO細胞生存率的影響……………………65
(三)銅離子對CHO細胞生存率的影響…………………………65
(四)同時添加HcyT與銅離子對CHO細胞生存率的影響……66
(五)同時添加HcyT與過氧化氫對CHO細胞生存率的影響……………………………………………………………….66
第七章 討論………………………………………………………...76
一、同半胱胺酸硫化內酯造成HL-60細胞程式凋亡…………76
二、抗氧化物及同半胱胺酸代謝營養素對同半胱胺酸硫化內酯引起HL-60細胞凋亡之影響………………………………79
三、不同類型細胞對同半胱胺酸硫化內酯的反應比較……….80
第八章 結論………………………………………………………...83
參考文獻……………………………………………………………84
附錄…………………………………………………………………93
表目錄
頁次
表6-1 添加銅離子對CHO細胞生存率的影響……………………69
表6-2 同時添加250 μM HcyT與銅離子對CHO細胞生存率的影響…………………………………………………………….70
表6-3 同時添加500 μM HcyT與銅離子對CHO細胞生存率的影響……………………………………………………………71
表6-4 同時添加1000 μM HcyT與銅離子對CHO細胞生存率的影響……………………………………………………….…………72
表6-5 同時添加250 μM HcyT與過氧化氫對CHO細胞生存率的影響……………………………………………………...……………73
表6-6 同時添加500 μM HcyT與過氧化氫對CHO細胞生存率的影響…………………………………………………………………74
表6-7 同時添加1000 μM HcyT與過氧化氫對CHO細胞生存率的影響…………………………………..……………………..……75
表附錄
頁次
附表1 低劑量HcyT或/和銅離子或同半胱胺酸的添加造成HL-60細胞內過氧化氫和超氧陰離子產生情形……………………………101
附表2 抗氧化物的添加對HcyT造成的HL-60細胞週期及細胞內相對蛋白質含量之影響………………………………………………102
附表3 高劑量同半胱胺酸代謝營養素的添加對HcyT造成的HL-60細胞週期及細胞內相對蛋白質含量之影響………………….103
圖目錄
頁次
圖一 同半胱胺酸衍生物之化學結構…………………….…………….25
圖二 同半胱胺酸代謝..…………………………….…………………26
圖三 活化caspase的兩條主要路徑………………………..……….27
圖4-1 定量HcyT造成HL-60細胞壞死………………..…………38
圖4-2 定量HcyT誘發HL-60程式凋亡之細胞膜傷害…….……39
圖4-3 HcyT對HL-60細胞生長週期及低染色體套數程式凋亡細胞之影響…………………………………………………..…………40
圖4-4 HcyT對HL-60細胞內蛋白質相對含量之影響…………..…41
圖4-5 HcyT造成HL-60細胞程式凋亡DNA斷片………………42
圖4-6 HcyT對HL-60細胞內過氧化氫產生之影響…….…………43
圖4-7 HcyT對HL-60細胞內超氧陰離子產生之影響…………44
圖4-8 HcyT對HL-60細胞內caspase-3活性之影響……………45
圖4-9 Caspase-9抑制劑及過氧化氫對HcyT活化HL-60細胞內caspase-3之影響…………………………..……..……46
圖4-10 Caspase-3抑制劑對HcyT引起HL-60細胞凋亡之影響..47
圖5-1 添加抗氧化物對HcyT誘發HL-60程式凋亡細胞膜傷害之影響………………………………………………………………….52
圖5-2 添加葉酸,維生素B6及B12對HcyT誘發HL-60細胞程式凋亡細胞膜傷害之影響……………………………………..……………53
圖5-3 抗氧化物的添加對HcyT造成HL-60程式凋亡DNA傷害之調節…………………………………………………………………54
圖5-4 維生素C的添加對HcyT造成HL-60程式凋亡DNA傷害之調節………………………………….……………………………..55
圖5-5 葉酸,維生素B6及B12的添加對HcyT造成HL-60程式凋亡DNA傷害之調節……………………………………………….………56
圖5-6 抗氧化營養素及同半胱胺酸代謝營養素對HL-60細胞因HcyT誘發DNA斷片產生之影響…………………………….……….57
圖5-7 抗氧化營養素對HL-60細胞內HcyT誘發過氧化氫產生之影響………………………………………………………..………58
圖5-8 葉酸,維生素B6及B12對HL-60細胞內HcyT誘發過氧化氫產生之影響…………………………………………………………..…59
圖5-9 抗氧化營養素對HL-60細胞內HcyT引起超氧陰離子產生之影響…………………………………………………………...………60
圖5-10 葉酸,維生素B6及B12對HL-60細胞內HcyT引起超氧陰離子產生之影響………………………………………………...……61
圖5-11 抗氧化物的添加對HcyT引起HL-60細胞caspase-3活化之影響………………………………………………………...………62
圖5-12 葉酸,維生素B6及B12的添加對HcyT引起的caspase-3活化之影響………………………………………………………….…63
圖6-1 添加過氧化氫對CHO細胞生存率的影響………………67
圖6-2 添加HcyT對CHO細胞生存率的影響…………………68
圖附錄
頁次
附圖1 添加過氧化氫對HL-60細胞內過氧化氫產生之影響……97
附圖2 添加過氧化氫對HL-60細胞內超氧陰離子產生之影響…98
附圖3 添加同半胱胺酸對HL-60細胞生存率的影響…………99
附圖4 添加同半胱胺酸對CHO細胞生存率的影響……………100
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