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研究生:陳威程
研究生(外文):Wei-Cheng Chen
論文名稱:異硫氰酸烯丙酯(AITC)影響細胞色素P450 2C9之研究
論文名稱(外文):Modulation of cytochrome P450 2C9 by allyl isothiocyanate (AITC)
指導教授:林雲冰
指導教授(外文):Yun-Ping Lim
學位類別:碩士
校院名稱:中國醫藥大學
系所名稱:藥學系碩士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:59
中文關鍵詞:細胞色素P450異硫氰酸藥物交互作用
外文關鍵詞:Drug drug interactionCytochrome P450AITCAllyl isothiocyanateCYP2C9
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藥物-藥物或藥物-食品交互作用常常會引起藥物不良反應,而藥物不良反應常見的原因是個體藥物代謝酶 ( drug-metabolizing enzymes, DMEs) 的表現差異不同而引起的。肝臟是人體最大的藥物代謝器官,其中細胞色素P450 2C9 (Cytochrome P450 2C9, CYP2C9) 為重要的代謝酶,主要受到細胞核接受體 (nuclear receptors, NRs) ,例如: 類酯醇X受體 (pregnane X receptor, PXR) 和構雄甾烷受體 (constitutive androstane receptor, CAR) 所調控。異硫氰酸烯丙酯 (allyl isothiocyanates, AITC) 大量存在於許多十字花科天然食品或保健食品中,常常用來抗癌或是抗菌,到目前為止很少研究去探討 AITC 跟細胞色素 P450 之間的相關性。在本研究中,我們主要目的是探討AITC是否藉由細胞核接受體來影響CYP2C9。利用西方墨點法及 Real Time-PCR 顯示AITC 抑制CYP2C9 蛋白質和mRNA的表現量;在reporter assay 顯示AITC破壞了核內接受體與共同活化因子之間的共同調控;經由 DNA affinity precipitation assay (簡稱DAPA) 顯示 AITC 有抑制核內接受體及共同活化因子結合在 CYP2C9 啟動子上。以上結果顯示,AITC 影響到 CYP2C9 的表現,可能會造成藥物在體內的血中濃度產生變化,對藥物安全性具有重要意義。

Drug - drug or drug - food interactions often lead to adverse drug reactions. Expression of drug-metabolizing enzymes (DMEs) is a common cause of adverse drug effects in some drugs. The liver is the largest organ in human, it contains multi-biological functions. Cytochrome P450 2C9 is predominantly regulated by nuclear receptors (NR), pregnane X receptor (PXR) and constitutive androstane receptor (CAR). Allyl isothiocyanate (AITC) is commonly found in cruciferous vegetables, with various biological activities, for example, anti-cancer and anti-bacterial. Until now, none of the report, study on the correlation between AITC with the cytochrome P450. In this study, we aimed to investigate the effect of AITC on the modulation of CYP2C9 through NRs. Using western blot and real time-PCR, we showed that AITC suppressed CYP2C9 protein and mRNA expression levels. AITC disrupted the coregulation effects of PXR/CAR with coactivation thus inhibited CYP2C9 reporter activities. By using DNA affinity precipitation assay, AITC inhibit nuclear receptors and related protein binding in CYP2C9 promoter. AITC will affect the CYP2C9 expression, the blood concentration of certain drugs may changed. Our results indicated that modification of CYP2C9 by consumption of AITC could have important implications on drug safety.

中文摘要 1
Abstract 2
表目錄 6
圖目錄 7
縮寫檢表 8
第一章 緒論 9
前言: 9
一、 細胞色素 P450 (Cytochrome P450, CYP450s) 9
二、 細胞色素 P450 2C9 (Cytochrome P450 2C9, CYP2C9) 10
三、 核內接受體 (Nuclear receptor, NR) 12
四、 類酯醇 X 受體 (Pregnane X receptor, PXR) 12
五、 構雄甾烷受體 (Constitutive androstane receptor, CAR) 14
六、 維甲酸 X 受體 (Retinoid X receptors α, RXRα) 15
七、 類固醇受體輔助因子 1 (Steroid receptor coactivator-1, SRC-1) 15
八、 肝細胞核因子 4 (Hepatocyte nuclear factor 4α, HNF4α) 16
九、 過氧化物酶體增殖物激活受體-γ 共激活因子 1 (Peroxisome
proliferator-activated receptor-gamma coactivator 1 alpha , PGC-1α) 16
十、 異硫氰酸烯丙酯 (Allyl isothiocyanates, AITC) 17
研究動機 20
第二章 研究方法 21
第一節 研究設計 21
第二節 實驗方法 22
細胞培養 (Cell culture) 22
細胞存活率試驗 (Assessment of cell viability) 22
西方墨點法 (Western blotting) 23
聚合酶連鎖反應 (Real Time polymerase chain reaction) 23
CYP2C9 報告基因分析 (CYP2C9 reporter assay) 24
DNA affinity precipitation assay (簡稱 DAPA) 24
統計分析 24
第三章 結果25
第四章 討論30
第五章 參考文獻33


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