Glutathione為KB細胞株中對抗亞砷酸鈉毒性 之主要物質

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王怡婷(Yi-Ting Wang) 查詢紙本館藏

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論文名稱

Glutathione為KB細胞株中對抗亞砷酸鈉毒性之主要物質
(Glutathione is a major participant in the defense of KB cells against NaAsO2-elicited toxicity)

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摘要(中)

近年來研究指出，砷化物的毒性作用機制之一為促使細胞內氧化壓
力(oxidative stress)的產生。本研究主要目的為探討三價無機砷
(NaAsO2, As(III))是否導致人類口腔癌細胞(KB cells)中超氧化物
(reactive oxygen species, ROS)含量上升以及其對於細胞內中各種抗氧
化物質之影響，並藉由專一性抑制劑與RNA 干擾技術分別抑制細胞
中抗氧化物質，以瞭解各種抗氧化物在砷化物毒性中所扮演的角色。
結果顯示，當細胞經不同濃度(0~40 ?M) 之As(III) 處理24 小時後，
細胞內的ROS 有隨著砷化物劑量增加而誘導生成之情形。進一步分
析細胞內抗氧化物質後發現超氧歧化酶(SOD)、榖胱甘肽過氧化酶
(GPX)之酵素活性與peroxiredoxins 的基因表現並無受到As(III) 之影
響。然而，榖胱甘肽轉移酶(GSTs)和觸酶(catalase)的酵素活性以及
GST?、perxiredoxin 6 的蛋白表現卻在高濃度As(III)處理下反而受到
抑制。僅有細胞內榖胱甘肽(GSH)之含量會被As(III) 所大量誘導生
成；進一步探討兩種GSH 生合成有關的蛋白glutathione reductase (GR)
以及?-glutamylcysteine synthase (?-GCS)，亦發現其基因與活性表現
皆會受到As(III)所誘導。利用抑制劑BSO 抑制細胞內GSH 的合成，
使得細胞對砷化物之毒性更加敏感，且在低濃度砷化物處理之下，就
會導致細胞內ROS 的顯著累積。因此本實驗推論KB 細胞對抗As(III)
之毒性，主要藉著誘導GSH 合成酶活性增加，進而使細胞內GSH 大
量表現以維持細胞氧化還原當量的平衡，並減少ROS 之累積以達到
保護細胞之功用。

摘要(英)

Arsenic is a common environmental toxicant and one of the plausible
mechanisms of arsenic toxicity is oxidative stress. Oxidative stress has
also been implicated as a possible etiologic factor for arsenic
carcinogenesis. The objective of this research is to study the effect of
sodium arsenite (NaAsO2, As(III)) on antioxidant defense activities in a
human carcinoma KB cell line. The results showed that the survival of
KB cells was decreased as the dose of As(III) increased. Moreover,
treatment of the cells with 0-40 ?M As(III) for 24 hours enhanced the
formation of cellular reactive oxygen species (ROS). However, these
treatments had no effect on the activities of superoxide dismutase (SOD)
and glutathione peroxidase (GPX) as well as on the mRNA expressions of
peroxiredoxins. Moreover, the activities of glutathione S-transferases
(GSTs), catalase and the protein levels of GST?, catalase and Prx6 were
down-regulated in As(III)-treated KB cells. In contrast, the level of
glutathione (GSH) represented the sole antioxidant that up-regulated in
KB cells by As(III) treatment. The results also showed that glutathione
reductase (GR) and ?-glutamylcysteine synthase (?-GCS) appeared to be
the major contributing factors to the higher level of GSH observed in
As(III)-treated cells. Depletion of GSH sensitized KB cells to As(III)
treatment and enhanced ROS formation in cells, while depletions of other
antioxidants had no significant effects on As(III)-induced cytotoxicity.
These results supported the hypothesis that GSH is a major participant in
the defense of KB cells against As(III)-elicited toxicity.

關鍵字(中)

★ 榖胱甘肽
★ 砷化物
★ 亞砷酸鈉
★ 抗氧化物
★ 氧化壓力
★ 酵素活性

關鍵字(英)

★ antioxidant
★ sodium arsenite
★ arsenic
★ glutathione
★ enzyme activity
★ reactive oxygen species
★ ROS

論文目次

Contents
中文摘要…………………………………………………………...….i
Abstract……...………………………………………………………..ii
Contents ………………………..………..………………….………...iii
Figure Contents ………….….……...……………………………....vi
Abbreviation ………….…….….…….……………………………...vii
Chapter 1. Introduction
1. Arsenic ………………………………………………………………..1
2. Arsenic-mediated ROS generation……………………………………2
3. Cellular antioxidants
3.1 Glutathione (GSH)…………………………………………………4
3.2 Glutathione-related enzymes……………………………………....4
3.3 Catalase…………………………………………………………….6
3.4 Superoxide dismutase (SOD)……………………………………...6
3.5 Peroxiredoxins (Prxs)……………………………………………...8
4. Specific aims………………………………………………………….9
Chapter 2. Materials and Methods
1. Cell culture…………………………………………………………..11
2. Arsenite (As(III)) treatment………………………………………….11
3. Cell viability assay…………………………………………………...11
4. Measurement of intracellular ROS…………………………………..12
5. Protein assay and quantification……………………………………..12
5.1 Cell extracts preparation………………………………………….12
5.2 Protein quantification…………………………………………….13
5.3 Sodium dodecyl Sulfate Polyacrylamide Gel Electrophoresis (SDS-PAGE) Analysis…………………………………………...13
5.4 Western blot analysis…………………………………………….13
6. Enzyme activity assay
6.1 Superoxide dismutase (SOD) activity assay……………………..15
6.2 Catalase activity assay……………………………………………15
6.3 Glutathione peroxidase (GPX) activity assay…………………….15
6.4 Glutathione S-transferases (GSTs) activity assay……………...…15
6.5 Glutathione (GSH) level assay…………………………………...16
6.6 Glutathione reductase (GSHR) activity assay……………………17
7. RT-PCR analysis
7.1 Total RNA isolation………………………………………………17
7.2 Reverse transcription (RT)………………………………………..18
7.3 Polymerase chain reaction (PCR)………………………………...18
8. Construction of Prx6 RNAi expression vector
8.1 siRNA target sequences design…………………………………...19
8.2 Anneal oligos……………………………………………………..21
8.3 Kinasing…………………………………………………………..21
8.4 p3in1 vector digestion and extraction…………………………….21
8.5 Ligate oligos into p3in1 vector………………………………...…22
8.6 Transformation……………………………………………………22
8.7 Colony-PCR and purification of plasmid DNA………………….23
8.8 DNA sequencing………………………………………………….23
9. Transfection…………………………………………………………..23
Results…………………………………………………………………25
Discussion……………………………………………………………..32
Figures………………………………………………………………....37
References…………………………………………………………….51
Appendix………………………………………………………….…..62

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指導教授

黃榮南(Rong-Nan Huang)

審核日期

2007-7-18

推文