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研究生:顏聖烈
研究生(外文):Yan, Sheng-Lei
論文名稱:飲食成分對乙醯氨酚引致的肝損傷及人類肝腫瘤細胞株影響的研究
論文名稱(外文):Effects of Dietary Components on Acetaminophen-induced Liver Injury and Human Liver Cancer Cell Lines
指導教授:吳淑姿吳淑姿引用關係
指導教授(外文):Wu, Shwu-Tzy
口試委員:張基郁殷梅津林俊哲余世宗吳淑姿
口試委員(外文):Chang, Chi-YueYin, Mei-ChinLin, Chun-CheYu, Shih-TsungWu, Shwu-Tzy
口試日期:2012-07-12
學位類別:博士
校院名稱:大葉大學
系所名稱:生物產業科技學系
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:2012
畢業學年度:100
語文別:中文
論文頁數:112
中文關鍵詞:組氨酸肌肽乙醯氨酚肝損傷齊墩果酸熊果酸凋亡肝腫瘤
外文關鍵詞:carnosinehistidineacetaminophenliver injuryoleanolic acidursolic acidapoptosisliver cancer
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本研究第一部分探討了組氨酸和肌肽對於乙醯氨酚引致的肝損傷的Balb/cA小鼠的保護作用。組氨酸或肌肽,分別以 0.5、1或2 g/L的濃度被加入飲用水中4週。小鼠的急性肝損傷是以腹腔內注射乙醯氨酚來產生。研究結果發現,乙醯氨酚的處理顯著減少肝臟中的穀胱甘肽以及抗壞血酸的水平,顯著增加肝臟中的丙二醛(malonyldialdehyde, MDA) 水平、活性氧物質 (ROS)、氧化型穀胱甘肽(GSSG),並且顯著減少肝臟中的穀胱甘肽過氧化酶(GPX)、過氧化氫酶 (CAT)、以及超氧化物歧化酶(SOD)的活性(P < 0.05)。然而,預先攝食組氨酸或肌肽能顯著減少乙醯氨酚引致的氧化壓力。其機轉是透過增加GSH,減少MDA、ROS和GSSG的形成,以及維持肝臟中GPX、CAT和SOD活性(P <0.05)。預先攝食組氨酸或肌肽能顯著降低乙醯氨酚引致的cytochrome P450 2E1活性增加(P < 0.05)。乙醯氨酚的處理能增加肝臟中的IL-6、 IL-10、TNF-α,以及單核細胞趨化蛋白-1 (MCP-1) (P < 0.05)。預先攝食組氨酸或肌肽能顯著降低乙醯氨酚引致的cytokines增加(P <0.05)。組氨酸或肌肽對於GPX、TNF-α以及MCP-1 mRNA的表現的影響顯示這兩種化合物的作用是在轉錄層級。本研究結果顯示組氨酸和肌肽是強效的肝炎保護劑。
本研究第二部分探討了齊墩果酸和熊果酸對四種人類肝腫瘤細胞株 HepG2、Hep3B、Huh7以及HA22T細胞株的促進凋亡的作用。齊墩果酸或熊果酸分別以 2、4或8 µmol/L的濃度來試驗對於肝腫瘤細胞株細胞存活、DNA fragmentation、粒線體膜電位、Na+-K+-ATPase活性、 caspase-3和capase-8的活性、細胞粘附,以及ICAM-1和VEGF水平的影響。齊墩果酸或熊果酸處理顯著降低HepG2和Hep3B細胞株的細胞存活,並且顯著增加DNA fragmentation,而且呈現concentration-dependent 的趨勢(P < 0.05)。然而,齊墩果酸和熊果酸只有在4 μmol/ L和8 μmol/ L時能顯著降低Huh7細胞株的細胞存活,以及增加DNA fragmentation (P < 0.05)。齊墩果酸或熊果酸處理顯著降低HepG2、Hep3B和HA22T細胞株的粒線體膜電位,而且呈現concentration-dependent 的趨勢 (P < 0.05)。齊墩果酸和熊果酸的處理顯著降低HepG2、Hep3B、HA22T、以及Huh7肝癌細胞株的Na+-K+-ATPase活性以及VEGF的水平,而且呈現concentration-dependent 的趨勢(P < 0.05)。齊墩果酸和熊果酸能顯著增加HepG2、Hep3B和HA22T細胞株的caspase-3和 capase-8的活性,而且呈現concentration-dependent 的趨勢(P < 0.05)。另外,齊墩果酸和熊果酸能顯著減少HepG2、Hep3B、以及Huh7細胞株的細胞粘附以及ICAM-1的水平,而且呈現concentration-dependent 的趨勢(P < 0.05)。這一部分的研究顯示齊墩果酸和熊果酸有強效的抗癌效果,能夠造成肝癌細胞株的凋亡。

In the first part of this study, protective effects of carnosine or histidine against acetaminophen-induced hepatotoxicity in Balb/cA mice were examined. Each compound, at 0.5, 1, or 2 g/L, was added into the drinking water for 4 weeks. Acute liver injury was induced by acetaminophen treatment intraperitoneally. Acetaminophen treatment significantly depleted hepatic GSH and ascorbic acid levels, increased hepatic level of malonyldialdehyde (MDA), reactive oxygen species (ROS), and oxidized glutathione (GSSG), as well as decreased hepatic activity of glutathione peroxidase (GPX), catalase, and superoxide dismutase (SOD) (P < 0.05). However, the pre-intake of carnosine or histidine significantly alleviated acetaminophen-induced oxidative stress by increasing GSH content, decreasing MDA, ROS, and GSSG formations, and retaining activity of GPX, catalase, and SOD in liver (P <0.05). The pre-intake of these compounds also significantly retarded subsequent acetaminophen-induced increase of cytochrome P450 2E1 activity (P < 0.05). Acetaminophen treatment increased the hepatic levels of interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, and monocyte chemoattractant protein (MCP)-1 (P < 0.05). The pre-intake of carnosine or histidine significantly diminished acetaminophen-induced elevation of these cytokines (P <0.05). The impact of these compounds on mRNA expression of GPX, TNF-alpha, andMCP-1 indicated that these compounds could act at a transcription level. These results support that carnosine and histidine are potent hepatoprotective agents.
In the second part of this study, apoptotic effects of oleanolic acid and ursolic acid on human liver cancer HepG2, Hep3B, Huh7 and HA22T cell lines were examined. OA or UA at 2, 4, 8 µmol/L were used and their effects on cell viability, DNA fragmentation, mitochondrial membrane potential (MMP), activity of Na+–K+-ATPase, caspase-3 and caspase-8, cell adhesion, level of intercellular adhesion molecule (ICAM)-1 and vascular endothelial growth factor (VEGF) in these cell lines were determined. OA or UA treatments concentration- dependently decreased cell viability and increased DNA fragmentation in HepG2 and Hep3B cell lines (P < 0.05). However, these two compounds reduced viability and increased DNA fragmentation in Huh7 cell only at 4 and 8 µmol/L (P < 0.05). OA or UA treatments concentration-dependently lowered MMP in HepG2, Hep3B and HA22T cell lines (P < 0.05). These two compounds also concentration-dependently diminished Na+–K+-ATPase activity and VEGF level in four test cell lines (P < 0.05). Besides Huh7 cell, OA or UA treatments concentration-dependently elevated caspase-3 and caspase-8 activities in other three cell lines (P < 0.05). Besides HA22T cell, these two compounds concentration-dependently inhibited cell adhesion and decreased ICAM-1 level in other three cell lines (P < 0.05). These findings support that OA and UA are potent anti-cancer agents to cause apoptosis in these liver cancer cell lines.


目錄

封面內頁
簽名頁
中文摘要……………………………………………………iii
英文摘要……………………………………………………v
誌謝…………………………………………………………vii
目錄…………………………………………………………viii
圖目錄………………………………………………………xii
表目錄………………………………………………………xiv

1. 緒論……………………………………………………1
2. 文獻回顧………………………………………………3
2.1藥物性肝損傷…………………………………………3
2.1.1 藥物性肝損傷流行病學…………………………3
2.1.2 藥物性肝損傷機轉………………………………6
2.1.3 造成藥物性肝損傷的藥物………………………7
2.1.4 乙醯氨酚引致的肝損傷…………………………9
2.1.5 乙醯氨酚代謝機轉………………………………10
2.1.6 乙醯氨酚引致的肝損傷的相關研究……………12
2.1.7 組氨酸和肌肽……………………………………17
2.2 肝癌…………………………………………………20
2.2.1 台灣肝癌現況……………………………………20
2.2.2 肝癌危險因子……………………………………21
2.2.3 肝癌的預防………………………………………28
2.2.4 肝癌治療…………………………………………30
2.2.5 肝癌細胞株的相關研究…………………………35
2.2.6 齊墩果酸和熊果酸………………………………38
3.材料與方法……………………………………………41
3.1組氨酸和肌肽在乙醯氨酚引致的肝損傷的保護作用…41
3.1.1 材料………………………………………………41
3.1.2 實驗設計…………………………………………41
3.1.3 丙氨酸轉氨酶,天門冬氨酸轉氨酶
和C -反應蛋白的分析…………………………42
3.1.4 α-生育酚及抗壞血酸的測量……………………42
3.1.5 穀胱甘肽和氧化型穀胱甘肽含量,超氧化物歧化酶
,過氧化氫酶和穀胱甘肽過氧化物酶活性測定……42
3.1.6 脂質氧化和活性氧物質的測定……………………42
3.1.7 Cytokines的測量…………………………………43
3.1.8 CYP2E1的活性測定…………………………………43
3.1.9 MCP - 1,TNF-α,和GPX mRNA表現的半定量
聚合酶鏈反應………………………………………45
3.1.10統計分析……………………………………………46
3.2 齊墩果酸和熊果酸對人類肝腫瘤細胞株的影響……46
3.2.1材料……………………………………………………46
3.2.2 肝癌細胞株培養……………………………………47
3.2.3 實驗設計……………………………………………47
3.2.4細胞存活試驗…………………………………………48
3.2.5測量 DNA fragmentation ...............48
3.2.6測定粒線體膜電位……………………………………48
3.2.7 Na+-K+-ATPase活性測定…………………………50
3.2.8 caspases活性測定…………………………………50
3.2.9粘附試驗………………………………………………51
3.2.10 分析血管內皮生長因子……………………………51
3.2.11 統計分析……………………………………………51
4.結果與討論…………………………………………………53
4.1組氨酸和肌肽在乙醯氨酚引致的肝損傷的保護作用……53
4.1.1組氨酸或肌肽處理對ALT和AST的影響………………53
4.1.2組氨酸或肌肽處理對CRP的影響……………56
4.1.3穀胱甘肽、氧化型穀胱甘肽、超氧化物歧化酶、
過氧化氫酶、和穀胱甘肽過氧化酶活性測定…56
4.1.4脂質氧化和活性氧物質(ROS)的測定………61
4.1.5 cytokines的測量……………………………61
4.1.6 CYP2E1的活性測定…………………………………65
4.1.7 MCP - 1,TNF-α,和GPX mRNA的表現………… 65
4.2 齊墩果酸和熊果酸對人類肝腫瘤細胞株的影響………68
4.2.1 細胞存活 (cell viability) 試驗……………68
4.2.2 DNA fragmentation....................70
4.2.3粒線體膜電位…………………………………73
4.2.4 Na+-K+-ATPase活性………………………75
4.2.5 caspases活性………………………………75
4.2.6粘附試驗…………………………………………………77
4.2.7血管內皮生長因子………………………………………80
5.結論……………………………………………………………86
5.1組氨酸和肌肽在乙醯氨酚引致的肝損傷的保護作用……86
5.2 齊墩果酸和熊果酸對人類肝腫瘤細胞株的影響…………87
參考文獻…………………………………………………………89
論文學術發表……………………………………………………113


圖目錄

圖1 乙醯氨酚的化學結構式………………………………5
圖2 乙醯氨酚的代謝路徑…………………………………11
圖3 組氨酸的化學結構式…………………………………18
圖4 肌肽的化學結構式……………………………………19
圖5 凋亡的訊息傳導路徑…………………………………34
圖6 齊墩果酸的化學結構式………………………………39
圖7 熊果酸的化學結構式…………………………………40
圖8 CYP2E1催化的p-nitrophenol羥基化反應………44
圖9 MTT assay.............................49
圖10 小鼠血清中ALT和AST的水平與給予組氨酸或肌肽處理間的關係………………………55
圖11 小鼠血清中CRP的水平與給予組氨酸或肌肽處理間的關係………………………………57
圖12 小鼠肝臟中GPX、 CAT 以及SOD的活性與給予組氨酸或肌肽處理間的關係…………60
圖13 小鼠肝臟微粒體CYP2E1的活性與給予組氨酸或肌肽處理間的關係……………………66
圖14 小鼠肝臟中TNF-alpha以及 MCP-1相對mRNA的表現與給予組氨酸或肌肽處理間的關係……67
圖15 小鼠肝臟中GPX相對mRNA的表現與給予組氨酸或肌肽處理間的關係……………………………69
圖16 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的細胞存活的影響………71
圖17 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的DNA fragmentation的影響………72
圖18 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的粒線體膜電位的影響…………………74
圖19 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的Na+-K+-ATPase活性的影響…………76
圖20 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的caspase-3的影響………………………78
圖21 齊墩果酸(OA)或熊果酸(UA)對人類正常肝細胞株及肝癌細胞株的caspase-8的影響………………………79
圖22 齊墩果酸(OA)或熊果酸(UA)對人類HepG2、Hep3B、Huh7和HA22T肝癌細胞株的細胞黏附的影響………81
圖23 齊墩果酸(OA)或熊果酸(UA)對人類HepG2、Hep3B、Huh7和HA22T肝癌細胞株的ICAM-1水平的影響……82
圖24 齊墩果酸(OA)或熊果酸(UA)對人類HepG2、Hep3B、Huh7和HA22T肝癌細胞株的的VEGF水平的影響……83

表目錄

表1 攝食0.5、1 或 2 g/L 組氨酸 (His) 或肌肽 (Car)的小鼠,在第1週及第4週的飲水量(WI, mL/mouse/d) 以及體重(g)........54
表2 以0.5、1 或 2 g/L 組氨酸 (His) 或肌肽 (Car) 前處理之後再給予或不給予乙醯氨酚(APAP) 的小鼠,其肝中GSH (nmol/mg protein),GSSG (nmol/mg protein),α-tocopherol (nmol/g tissue),以及 ascorbic acid (nmol/mg tissue) 的含量…………………………………58
表3 以0.5、1 或 2 g/L 組氨酸 (His) 或肌肽 (Car) 前處理之後再給予或不給予乙醯氨酚(APAP) 的小鼠,其肝中MDA (μmol/L) 及ROS(nmol/mg protein) 的含量………………………………………………………………………………………………………………………………………………………62
表4 以0.5、1 或 2 g/L 組氨酸 (His) 或肌肽 (Car) 前處理之後再給予乙醯氨酚(APAP)的小鼠,其肝中TNF-α,IL-6,IL-10,以及MCP-1的含量(pg/mg protein)........................................................................................................63



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