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系統識別號 U0007-2507201114513200
論文名稱(中文) 右旋兒茶素作用於順氯氨鉑引發腎毒性小鼠之蛋白質體分析
論文名稱(英文) Proteome Analysis of Cisplatin Nephrotoxicity in Mice with (+)-Catechin Treatment
校院名稱 臺北醫學大學
系所名稱(中) 藥學研究所
系所名稱(英) Graduate Institute of Pharmacy
學年度 99
學期 2
出版年 100
研究生(中文) 巫蕙宜
研究生(英文) Hui-Yi Wu
學號 M301098005
學位類別 碩士
語文別 中文
口試日期 2011-07-11
論文頁數 89頁
口試委員 委員-陳福安
委員-蔡東湖
委員-李宗徽
委員-陳世銘
指導教授-李仁愛
中文關鍵字 蛋白質體學  順氯氨鉑腎毒性  (+)-兒茶素  螢光高效能液相層析  液相層析-串聯質譜 
英文關鍵字 proteomics  cisplatin nephrotoxicity  (+)-catechin  ROS  FD-HPLC  LC-MS/MS 
學科別分類
中文摘要 順氯氨鉑(cis-diamminedichloroplatinum (II), CDDP)是目前廣泛應用於治療固體癌的化學治療藥物之一,然而在臨床上的應用常受限於其腎毒性。先前的研究已證實(+)-catechin對於CDDP造成的腎毒性具有保護的效果。本研究利用蛋白質體學的研究方法,比較以CDDP誘導腎毒性小鼠與服用抗氧化藥物(+)-catechin小鼠腎臟組織蛋白質表現差異,希望能釐清(+)-catechin對於腎臟的保護機轉,也期望從中找到臨床上可使用的生物標記來早期診斷腎損傷的發生。
在施打CDDP前5天開始經口投予(+)-catechin作為預防藥物,持續投藥直至動物犧牲前,對照組經口投予蒸餾水 0.1 ml/mice。在CDDP 5 mg/kg/d連續3天及5天腹腔投予BALB/c小鼠後,將小鼠予以犧牲。取出小鼠腎臟將之均質後,加入螢光衍生化試劑4-[2-(dimethylamino)ethylaminosulfonyl]-7- chloro-2,1,3-benzoxadiazole (DAABD-Cl),利用螢光高效能液相層析法分析。之後,利用LC-MS/MS定性表現量產生變化的蛋白質,並以MASCOT資料庫比對蛋白質。
實驗結果顯示,連續給予CDDP 3天的小鼠相較於給予預防藥物的小鼠之腎臟,共有44個蛋白質表現量有顯著差異(P < 0.05);連續給予CDDP 5天的小鼠相較於給予預防藥物的小鼠之腎臟,則有9個蛋白質表現量具有顯著差異(P < 0.05)。實驗中定性之蛋白質可依功能分為數個種類,包括:運輸蛋白、抗氧化酵素、 ATP 合成相關蛋白、抗發炎蛋白 、細胞凋亡相關蛋白、細胞骨架及 DNA結合蛋白等。
本研究證實(+)-catechin可藉由增加體內抗氧化酵素活性,抑制發炎反應、抑制MAPK pathway等機轉,達到腎臟保護的效果。另一方面也發現,細胞在遭受外來壓力時,會啟動自我保護機制,減少細胞毒性物質進入細胞中(OCT2表現量下降),並增加細胞毒性物質輸出量(ABC transporter表現量上升)以調適外來的傷害。
總結本研究的結果,可更加了解腎臟組織受損與修復之間蛋白質表現量的變化,對於日後CDDP腎毒性機轉之研究以及保護腎臟藥物之開發具有很大的意義。
英文摘要 Cisplatin (CDDP) has emerged as a principal chemotherapeutic agent in the treatment of various solid tumors. However, the full clinical utility of CDDP is limited due to its dose-related nephrotoxicity. In our previously study, (+)-catechin (CAT) acted as a protective agent against CDDP nephrotoxicity. To understand the protection mechanism of CAT in CDDP-induced nephritis, the aim of this study was to identify the altered proteins between CDDP-induced nephritis group and with CAT prevention group. Moreover, to find out some biomarkers to predict kidney injury effectively.
Before administration of CDDP (i.p. 5 mg/kg/d on day 1 to day 5), BALB/c mice (6 week, female) were administered orally with CAT 50 mg/kg once daily for 10 days (on day -5 to day 5, i.e. treat for 5 days) and 8 days (on day -5 to day 3, i.e. treat for 3 days). The homogenate of the kidney was derivatized with 4-[2-(dimethylamino)ethylaminosulfonyl]-7- chloro-2,1,3-benzoxadiazole (DAABD-Cl), and subjected to proteome analysis by Fluorogenic Derivatization-High-Performance Liquid Chromatography (FD-HPLC). Finally, the altered proteins were identified by LC-MS/MS with MASCOT database searching system.
The results showed that proteins changed significantly in both 3 days and 5 days samples. Between the CDDP and CAT tissues of the 3-day and 5-days treatment group, 44 proteins and 9 proteins had significantly difference in expressions (P < 0.05), respectively. The proteins found in this study can be separated into several categories: transporter, antioxidase, ATP-synthesis, anti-inflammatory, apoptotic, cell skeleton, DNA binding protein.
Our finding demonstrated that CAT can attenuate CDDP-induced nephrotoxicity by increasing antioxidase level, suppressing inflammation, and inhibition of MAPK signaling pathway. On the other hand, transporter associated with CDDP transport into cells was downregulated, and transporter associated with CDDP transport out of cells was upregulated, suggesting a defense response against subsequent exposure and renal uptake of CDDP.
In conclusion, this study may serve to find new biomarkers to improve early detection and new drug development in CDDP-induced nephrotoxicity.
論文目次 目錄 I
附圖目錄 III
附表目錄 IV
縮寫表 V
中文摘要 VII
Abstract IX
第一章 緒言 1
第二章 文獻回顧 4
第一節 順氯氨鉑 (Cisplatin) 4
第二節 Cisplatin引起腎毒性的表徵 9
第三節 Cisplatin引起腎毒性之機轉 11
第四節 綠茶主成分(+)-catechin藥效研究 20
第五節 蛋白質體學 25
第三章 研究目的 32
第四章 材料與方法 36
第一節 實驗試藥、耗材與儀器 36
1.1 實驗試藥 36
1.2 耗材與儀器 36
第二節 實驗動物 39
2.1 組織來源 39
2.2 飼養流程 39
第三節 實驗方法 41
3.1 小鼠腎臟組織之蛋白質分離 41
3.2 小鼠腎臟組織之蛋白質定性 45
第五章 結果 50
第一節 差異波峰比對 50
第二節 蛋白質定性結果 53
第六章 討論 58
6.1 Regulatory solute carrier protein, family 1, member 1 58
6.2 ABC transporter 59
6.3 Cu/Zn superoxide dismutase 60
6.4 Antioxidant protein 1 62
6.5 Lysozyme 65
6.6 Diazepam binding inhibitor isoform 2 67
6.7 NADH dehydrogenase 68
6.8 α-fetoprotein 71
6.9 Pleckstrin and sec7 domain 3 72
6.10 α-2-HS-glycoprotein 73
6.11 Histone cluster 1 75
6.12 Dynein, heavy chain 8 77
6.13 Spectrin, non-erythroid beta chain 4(BSPEC-V) 77
6.14 Glial fibrillary acidic protein 78
6.15 小結 79
第七章 結論 81
參考文獻 82


附圖目錄
圖 一、台灣地區主要死因死亡趨勢圖 3
圖 二、Cis-diamminedichloroplatinum (II)之化學結構式 4
圖 三、CDDP與DNA結合方式示意圖 8
圖 四、CDDP引起之腎毒性的主要機轉 17
圖 五、死亡接受器示意圖 18
圖 六、細胞凋亡訊息傳遞路徑 19
圖 七、各種兒茶素的結構 24
圖 八、碰撞誘導解離示意圖 30
圖 九、(+)-Catechin在CDDP之腎炎模型對NAG的分析 34
圖 十、(+)-Catechin在CDDP之腎炎模型對Ucr.的分析 34
圖 十一、(+)-Catechin在腎炎模型腎組織型態變化情形 35
圖 十二、DAABD-Cl之化學結構式與衍生化反應過程 43
圖 十三、串聯質譜分析儀示意圖 47
圖 十四、MASCOT搜尋引擎參數設定表示圖 49
圖 十五、小鼠腎臟組織之HPLC層析圖譜 52
圖 十六、CDDP小鼠與 Catechin小鼠蛋白表現量比較圖 57
圖 十七、CDDP小鼠與正常小鼠間SOD1表現量之差異 61
圖 十八、PRDXs之結構,分佈位置與電子供應者 63
圖 十九、LZ抑制細胞凋亡示意圖. 66
圖 二十、呼吸作用的過程 67
圖 二十一、電子傳遞鏈 70
圖 二十二、順氯氨鉑與反氯氨鉑之化學結構式 75
圖 二十三、Histone cluster 1在CDDP小鼠與正常小鼠間表現量差異 76
圖 二十四、GFAP在CDDP小鼠與正常小鼠間表現量差異 79


附表目錄
表 一、順氯氨鉑在腎功能不良的病人身上的劑量調整 6
表 二、CDDP使用時,水分的補充及利尿劑的使用 7
表 三、(+)-catechin在腎炎模型之BUN值 35
表 四、蛋白質定性結果 53
表 五、已鑑定蛋白在各時間點的變化情況 80

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