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系統識別號 U0026-2807201115414100
論文名稱(中文) Allyl isothiocyanate及其它辛香料成分對於細胞色素3A4基因表現和酵素活性的影響
論文名稱(英文) The effect of allyl isothiocyanate and other ingredients of spices on CYP3A4 gene expression and enzyme activity
校院名稱 成功大學
系所名稱(中) 藥理學研究所
系所名稱(英) Department of Pharmacology
學年度 99
學期 2
出版年 100
研究生(中文) 張慧美
研究生(英文) Hui-Mei Chang
學號 s26984113
學位類別 碩士
語文別 中文
論文頁數 79頁
口試委員 指導教授-黃金鼎
共同指導教授-賴明亮
口試委員-周辰熹
中文關鍵字 細胞色素  辛香料 
英文關鍵字 spice  allyl isothiocyanate  CYP3A4  PXR 
學科別分類
中文摘要 細胞色素P450是可以將外來物質進行氧化代謝以利外來物質排除體外的酵素,CYP3A4是其中很重要的成員,並且參與約百分之五十以上臨床用藥的代謝。CYP3A4的表現量及活性差異是藥物交互作用的主要原因,CYP3A4在個體之間的高度變異性也會增加臨床用藥的困難度,而在個體之間CYP3A4表現量或活性的差異可能是因為基因上的變異或外在環境的因素,但大多數的CYP3A4基因變異並不會對蛋白質有顯著影響,且不足以解釋個體之間的高度變異性,因此後天環境因素,例如藥物或食物,對於CYP3A4表現量、酵素活性及基因轉錄上的影響就顯得很重要。已知 Pregnane X receptor (PXR) 會受到外來藥物的活化而正向調控CYP3A4的基因;而抗黴菌藥物ketoconazole會藉由破壞 PXR和共同活化子steroid receptor coactivator-1(SRC-1)之間的交互作用,負向調控CYP3A4的基因,降低CYP3A4 mRNA以及蛋白質的表現量。在我們日常生活的飲食中,經常添加辛香料以增加食物的風味,我們預測辛香料的成分也有可能直接影響CYP3A4的酵素活性或是透過PXR而影響CYP3A4的基因調控及蛋白質表現量。
我們在人類肝癌細胞(HepG2 cells)中利用CYP3A4啟動子報導基因分析方法篩選辛香料的成分,已知rifampin可以活化PXR,並透過PXR調控路徑而增加CYP3A4基因啟動子的活性,因此我們以rifampin做為positive control,從中發現了芥子、辣根、山葵及其他十字花科植物中的成分:allyl isothiocyanate (AITC),它會抑制原本由rifampin透過PXR增加的CYP3A4啟動子報導基因活性,但是對於CYP3A4的mRNA及蛋白質表現量並沒有顯著的影響,使用人類結腸癌細胞(LS174T cells)做確認後發現結果與人類肝癌細胞(HepG2 cells)中相同,接著利用P450-Glo™ assay來測量CYP3A4的酵素活性,發現在人類肝癌細胞(HepG2 cells)中,AITC在較高濃度(30 μM)時可以抑制CYP3A4的酵素活性約40%,而在人類結腸癌細胞(LS174T cells)中則是抑制約20%,因此AITC有些許的可能性會導致食物與藥物間的交互作用以及為個體間CYP3A4酵素活性的差異做一小部分的解釋,但仍然需要in vivo的實驗來證實此可能性。AITC最終對於CYP3A4蛋白質表現量並沒有顯著的影響可能是因為除了PXR之外還有其他轉錄因子會結合到CYP3A4的基因上,CYP3A4基因的最終調控情況是所有結合到CYP3A4啟動子之轉錄因子共同調節作用的總合。
英文摘要 Cytochrome P450 monooxygenases (CYPs) can catalyze the oxidation of xenobiotics and facilitate their elimination. One of the most important enzyme is CYP3A4 which metabolizes more than 50% of clinical used drugs. The major role of CYP3A4 in xenobiotic metabolism and the large interindividual variability contributes to both the low therapeutic success of drugs and the harmful drug interactions. Interindividual differences in enzyme expression or activity may be due to genetic mutations and environmental stimuli. CYP3A4 polymorphisms that result in functionally altered protein variants are rare and also insufficient to explain the large interindividual variation of CYP3A4 enzyme levels or activity. Thus, the large interindividual variation of CYP3A4 enzyme levels or activity may be related to environmental factors such as drug intake or diet. Pregnane X receptor (PXR) can be activated by a large number of xenobiotics and regulate drug metabolism enzyme such as CYP3A4. Ketoconazole, a clinically used antifungal compound, can inhibit CYP3A4 through the transcription of gene regulated by disrupting PXR interaction with steroid receptor coactivator-1(SRC-1). Spices are often used in foods to improve the taste of them. We predicted the ingredients of spices may cause the changes in CYP3A4 enzyme expression through PXR or affect CYP3A4 enzyme activity directly.
We established CYP3A4 luciferase reporter assays in HepG2 cell line to assess the effect of several ingredients of spices on CYP3A4 promoter activity. Rifampin, which can increase PXR activity and activate the PXR-mediated CYP3A4 gene expression, was used as positive control. We found allyl isothiocyanate (AITC), a ingredient of mustard, horseradish, wasabi and other cruciferous vegetables, decreased reporter acitivity on rifampin-mediated activation in a concentration-dependent manner. But CYP3A4 mRNA level and protein expression had no significant changes by treating HepG2 cells with AITC. The results in the other cell line (LS174T) were similar to the results in HepG2 cells. We further explored the ability of AITC to inhibit enzyme activity of CYP3A4, using P450-Glo™ assay. AITC resulted in approximately 40% reduction of CYP3A4 enzyme activity in HepG2 cells and 20% reduction in LS174T cells only at a higher concentration (30 μM). Thus, AITC may contribute to a fraction of interindividual variation in CYP3A4 enzyme activity and have some potential to cause food-drug interactions. But it needs more experiments in vivo to confirm the possibility. AITC didn’t cause significant changes in CYP3A4 protein expression may due to other transcription factors binding other than PXR. The responsiveness of the CYP3A4 gene to xenobiotics represents the summation of modulatory effects from all of the transcription factors binding to the promoter region.
論文目次 中文摘要 I
Abstract III
誌謝 V
目錄 VI
表目錄 VIII
圖目錄 IX
縮寫檢索表 XI
第一章 緒論 1
一、前言 1
二、細胞色素P450 (Cytochrome P450) 1
三、細胞色素 3A4 (Cytochrome P450 3A4;CYP3A4) 2
四、類酯醇X受體 (Pregnane X receptor;PXR) 4
五、PXR影響CYP3A4表現的機制 5
六、Allyl isothiocyanate (AITC)之介紹 6
七、研究目的 9
第二章 實驗材料 10
一、化學物品及試劑 10
二、試劑組 13
三、酵素 14
四、抗體 14
五、細菌培養相關材料及抗生素 14
六、細胞培養相關材料 15
七、實驗儀器 17
八、其它材料 17
第三章 實驗方法 18
一、實驗藥品配製 18
二、細胞培養 18
三、細胞存活率測定 19
四、CYP3A4酵素活性測定 19
五、質體建構 20
六、短暫性轉染及CYP3A4 啟動子報導基因分析 20
七、CYP3A4 mRNA表現量分析 22
八、CYP3A4 蛋白質表現量分析 26
第四章 實驗結果 29
一、利用CYP3A4 啟動子報導基因分析方法篩選辛香料的成分 29
二、Allyl isothiocyanate (AITC)不會抑制CYP3A4的mRNA表現量 30
三、Allyl isothiocyanate (AITC)不會抑制CYP3A4的蛋白質表現量 30
四、Allyl isothiocyanate (AITC)對於CYP3A4酵素活性的影響 31
第五章 結論與討論 32
一、結論 32
二、討論 33
參考文獻 41

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