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研究生:朱鼎諺
研究生(外文):Ting-Yen
論文名稱:馬兜鈴酸在人類腎細胞株所誘發的氧化壓力及其影響
論文名稱(外文):Induction of oxidative stress by Aristolochic acid in human renal proximal tubular epithelial cell line
指導教授:劉秉慧張浤榮張浤榮引用關係
指導教授(外文):Biing-Hui LiuHorng-Rong Chang
學位類別:碩士
校院名稱:中山醫學大學
系所名稱: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:2009
畢業學年度:97
語文別:中文
論文頁數:78
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馬兜鈴酸 (Aristolochic acid, AA) 是由馬兜鈴屬的植物所萃取出來的天然成份之一,此萃取混合物主要由Aristolochic acid I (AAI) 和Aristolochic acid II (AAII) 所組成,前人研究發現馬兜鈴酸會導致中草藥腎病變 (CHN) 並且具有腎毒性和致癌性。在本篇論文中探討AAI是否會促使人類腎臟細胞生成活性氧分子(ROS),以及AAI的致毒機轉是否和ROS的產生具有關聯性。我們以人類腎近曲小管上皮細胞株 (HK-2) 為研究模式,當AAI的劑量在100 μM到200 μM之間會導致HK-2細胞的存活率下降,以200 μM AAI處理HK-2細胞18小時則會造成細胞中ROS的生成量顯著上升,但是若以抗氧化劑麩胱甘肽 (GSH) 前處理細胞後,則發現GSH能有效抑制AAI所誘發的ROS產生。此外,利用單細胞凝膠電泳分析則觀察到當 AAI濃度達到50 μM以上時即可令HK-2細胞核中發生DNA斷裂 (DNA breakage) 的傷害,但是抗氧化劑GSH的存在並不會減少AAI所誘導的DNA損傷,由此顯示AAI所引起的DNA損壞並不是藉由ROS所調控。另一方面,若是以50 μM以上的AAI處理人類急性前骨髓白血病細胞株 (HL-60),則發現細胞內的鈣離子濃度會隨著AAI的劑量提高而顯著降低。從細胞保護機制的角度觀察,利用螢光酵素報導基因 (luciferase reporter gene) 分析得知AAI的處理能夠藉由活化HK-2細胞內的Nrf2結合序列來提高下游luciferase的酵素活性,因此推論AAI可能藉由活化Nrf2結合序列,進而調控下游抗氧化酵素活化來抵抗AAI所造成的傷害。
在另一方面,我們進一步探討ROS生成與MAPKs訊息傳遞路徑之間的關聯性。以200 μM AAI處理HK-2細胞會令細胞內ERK1/2和p38磷酸化的訊號增強,然而當抗氧化劑GSH與毒素共存時無法抑制AAI所誘發的ERK1/2和p38磷酸化,顯示AAI所引發的ROS產生並非活化ERK1/2和p38訊號途徑的上游因子。但是若以MEK1/2抑制劑U0126前處理HK-2細胞,不但會抑制AAI所活化的ERK1/2磷酸化,也會同時降低AAI誘發的ROS生成量,顯示AAI藉由MEK/ERK1/2的訊息傳遞途徑而促使ROS的產生。此外,不論是p38抑制劑SB202190或是MEK1/2抑制劑U0126的存在皆能降低AAI所引起的DNA損傷,由此得知AAI所造成的DNA傷害與細胞中ERK1/2和p38途徑的活化有著密切的相關性。

Aristolochic acid (AA), a natural ingredient extracted from species Aristolochia, is composed of AAI and AAII. AAI is reported to be related to Chinese herb nephropathy (CHN), renal toxicity and carcinogenicity. To investigate whether AAI induce the generation of ROS and the toxicological relationship between AA and ROS, human proximal tubule epithelial cell line (HK-2) was chosen in our study. AAI (100 μM - 200 μM) treatment for 24 hours caused a marked decrease in the cell viability of HK-2. The ROS levels in HK-2 cells were also significantly induced by 200 μM AAI. The presence of antioxidant glutathione (GSH) effectively inhibited the ROS generation induced by AAI. Furthermore, in single cell gel electrophoresis assay, AAI at a concentration reached 50 μM resulted in the DNA damage in HK-2 nucleus. However, AAI-induced DNA damage was not suppressed by the co-existence of GSH. These results showed that AAI-induced DNA damage was not modulated by ROS generation. On the other hand, when human promyelocytic leukemia cell line (HL-60) was treated with AAI, the calcium concentration in HL-60 was significantly decreased in a dose-dependent manner. In view of cellular protective mechanism, with luciferase reporter assay we found that the Nrf2 binding elements were activated by AAI, which suggesting that AAI regulated the downstream antioxidant enzymes to against damage via activation of Nrf2 binding element.
We further investigated he relationship between ROS and MAPKs signaling pathway. AAI induced the signals of phosphorylated ERK1/2 and p38 in HK-2 cells, but the presence of GSH could not effectively inhibit the phosphorylated signals induced by AAI. These results demonstrated that AAI-induced ROS is not a major upstream factor of ERK1/2 and p38 pathway. On the other hand, MEK1/2 inhibitor, U0126, dramatically decreased the AAI-induced phospho-ERK1/2 and ROS generation in HK-2 cells, indicating that AAI may mediate the ROS generation via MEK/ERK1/2 signaling pathway. Moreover, either p38 or ERK1/2 inhibitor reversed the DNA damage induced by AAI. These results implied that both ERK1/2 and p38 pathways play important roles in AAI-induced DNA damage.

目錄

中文摘要------------------------------------------------------------------------ 01
英文摘要------------------------------------------------------------------------ 03
序論------------------------------------------------------------------------------ 05
馬兜鈴酸的毒性------------------------------------------------------------ 05
活性氧分子------------------------------------------------------------------ 09
Nuclear factor-erythroid 2 related factor 2 (Nrf2)---------------------- 13
鈣離子訊息傳遞和ROS的關聯---------------------------------------- 16
ERK1/2訊息傳遞路徑和ROS的關聯--------------------------------- 18
p38訊息傳遞路徑與ROS的關聯-------------------------------------- 22
研究動機與方向------------------------------------------------------------ 24
材料與方法--------------------------------------------------------------------- 25
試劑--------------------------------------------------------------------------- 25
細胞株------------------------------------------------------------------------ 25
細胞培養--------------------------------------------------------------------- 26
細胞存活率MTT試驗---------------------------------------------------- 26
偵測活性氧分子------------------------------------------------------------ 27
單細胞凝膠電泳分析------------------------------------------------------ 28
偵測細胞凋亡蛋白3的活性--------------------------------------------- 29
全蛋白質萃取--------------------------------------------------------------- 30
西方點墨法------------------------------------------------------------------ 31
偵測細胞內鈣離子濃度--------------------------------------------------- 33
基因轉殖--------------------------------------------------------------------- 34
螢光酵素報導基因分析--------------------------------------------------- 34
實驗結果------------------------------------------------------------------------ 36
一、AAI造成HK-2細胞的細胞存活率下降------------------------ 36
二、AAI造成HK-2細胞株生成活性氧分子------------------------ 36
三、麩胱甘肽抑制AAI所誘發的ROS產生------------------------ 38
四、AAI活化HK-2細胞株中的Caspase 3-------------------------- 41
五、AAI造成HK-2細胞株DNA的損傷---------------------------- 42
六、GSH無法抑制AAI所誘發的DNA傷害----------------------- 44
七、AAI活化Nrf-2結合序列所驅動的luciferase酵素活性----- 44
八、AAI無法活化HK-2細胞株的HO-1基因活性---------------- 47
九、AAI降低HL-60細胞株的細胞內鈣離子濃度----------------- 49
十、AAI導致HK-2細胞株中ERK1/2與p38磷酸化------------- 49
十一、GSH無法抑制AAI引發的ERK1/2與p38磷酸化-------- 53
十二、MEK1/2抑制劑U0126抑制AAI所誘發的ROS產生--- 56
十三、U0126與SB202190抑制AAI引發的DNA傷害---------- 59
討論------------------------------------------------------------------------------ 61
參考文獻------------------------------------------------------------------------ 65

圖次

圖一、AAI造成HK-2細胞株的細胞存活率下降---------------------- 37
圖二、AAI造成HK-2細胞株生成活性氧分子------------------------- 39
圖三、麩胱甘肽 (GSH) 抑制AAI所誘發的ROS產生-------------- 40
圖四、AAI活化HK-2細胞株中的Caspase 3--------------------------- 43
圖五、AAI造成HK-2細胞株DNA的損傷----------------------------- 45
圖六、GSH無法抑制AAI所誘發的DNA傷害------------------------ 46
圖七、AAI活化Nrf-2結合序列所驅動的luciferase酵素活性------ 48
圖八、AAI無法活化HK-2細胞株的HO-1基因活性----------------- 50
圖九、AAI降低HL-60細胞株的細胞內鈣離子濃度------------------ 51
圖十、AAI導致HK-2細胞株中ERK1/2與p38磷酸化-------------- 54
圖十一、GSH無法抑制AAI引發的ERK1/2與p38磷酸化-------- 55
圖十二、U0126抑制AAI引發的ERK1/2磷酸化--------------------- 57
圖十三、MEK1/2抑制劑U0126抑制AAI所誘發的ROS產生---- 58
圖十四、U0126與SB202190抑制AAI引發的DNA傷害---------- 60
附圖一、AAI和AAII的結構式------------------------------------------- 06
附圖二、活性氧分子的種類與生成途徑--------------------------------- 10
附圖三、Nrf2蛋白質序列--------------------------------------------------- 14
附圖四、氧化壓力與ERK1/2訊息傳遞路徑的關聯------------------- 21
附圖五、氧化壓力和p38訊息傳遞路徑的關聯------------------------ 23


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