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系統識別號 U0026-0508201215581900
論文名稱(中文) 細胞色素3A5以及雌激素對於細胞色素3A4表現量的影響
論文名稱(英文) Effect of CYP3A5 and estradiol on the expression level of CYP3A4
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 100
學期 2
出版年 101
研究生(中文) 林欣瑩
研究生(英文) Hsin-Ying Lin
學號 s26991021
學位類別 碩士
語文別 中文
論文頁數 67頁
口試委員 指導教授-黃金鼎
指導教授-賴明亮
口試委員-周辰熹
中文關鍵字 細胞色素3A4  細胞色素3A5 
英文關鍵字 CYP3A4  CYP3A5  estradiol  1 alpha,25-(OH)2-D3 
學科別分類
中文摘要 Cytochrome P450對於生物體內生性化合物的氧化作用及外來物質的生物轉化(biotransformation)作用等代謝過程扮演著重要的角色。其中CYP3A4主要表現在肝臟及小腸中,而CYP3A5則主要表現在腎臟、肺臟等肝外組織。CYP3A5在個體間表現量的差異頗大,而此差異性多源自於基因多型性的關係。CYP3A5基因有許多單一核苷酸變異(single nucleotide polymorphism,SNP),SNP的allele為CYP3A5*3時,由於intron 3的6986位置發生A>G的單點突變,因此導致組織中CYP3A5的表現量減低。本實驗室先前研究發現無論在模擬小腸(Caco-2)或是肝臟(HepG2)的細胞體外模式下,CYP3A4酵素在mRNA及蛋白質的表現量並不會因不同的CYP3A5表現量而有所改變。而先前研究指出,在動物模式中,當大量表現CYP3A4時,可使estradiol被代謝的量上升,進而回饋使CYP3A4量下降。因此,本計畫中我們推論在CYP3A5*3的個體,由於CYP3A5蛋白質表現量較低,在代謝特定受質時可能會經由某些機制增加CYP3A4同功能性酵素蛋白的表現,以代償CYP3A5酵素的缺失。
我們將利用Caco-2 和HepG2兩種細胞株加入不同濃度的estradiol之後觀察CYP3A4和CYP3A5蛋白表現量,進一步利用短暫性轉殖CYP3A5針對CYP3A5量的提升去觀察CYP3A4表現量,配合研究estradiol因CYP3A4表現量而影響其代謝程度,並深入探討CYP3A4和CYP3A5間特殊的調控機制。
英文摘要 People without CYP3A5 expression was supposed to have a higher plasma concentration and lower clearance of drugs. However, our laboratory previously showed that CYP3A5*3 genotype affects the protein level of CYP3A5 but does not influence the midazolam metabolism in clinical data. Recent studies have demonstrated that CYP3A5*1/*3 (positive) male subjects exhibited a higher nifedipine (immediate-release form, Adalat® ) plasma concentration than CYP3A5*3/*3 (negative) male subjects but not for female subjects on slow-release nifedipine administrate. CYP3A4 level seemed to be up-regulated in some of homozygous CYP3A5*3 subjects. In human CYP3A4-transgenic (Tg-CYP3A4) mice, overexpression of CYP3A4 enhanced estradiol metabolism. Upregulation of estradiol metabolism decreased CYP3A4 by feedback inhibition. From above, CYP3A4 expression level was affected by CYP3A5 and estradiol. Therefore we want to study the role of CYP3A5 and estraiol in drug metabolism and expression level of CYP3A4. In this study CYP3A4 protein level was not affected by treating with estradiol or CYP3A5 overexpression in Caco-2 and HepG2 cells. Interestingly, CYP3A4 protein level was affeced by CYP3A5 overexpression cells together with various concentrations of estradiol. Moreover, previous studies show that 1 alpha,25-(OH)2-D3, vitamin D receptor (VDR) ligand, promotes CYP3A4 expression. In order to study the effect of CYP3A5, we observed CYP3A4 expression level affected by cotreatment of estradiol and VDR ligand in CYP3A5 overexpression cells. Above data indicate that CYP3A5 affect CYP3A4 expression level under the circumstances.
論文目次 中文摘要 ………………………………………………………… Ⅰ
Abstract ………………………………………………………… Ⅲ
致謝 ………………………………………………………………… Ⅳ
目錄 ……………………………………………………………… Ⅴ
表目錄 …………………………………………………………… Ⅶ
圖目錄 …………………………………………………………… Ⅷ
縮寫檢索表 ………………………………………………………… Ⅸ
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、細胞色素3A5(Cytochrome P450 3A5;CYP3A5) ………………5
五、雌激素(Estradiol)之介紹 …………………………………7
六、研究目的 …………………………………………………8
第二章 實驗材料 …………………………………………………10
一、化學藥品及試劑 …………………………………………10
二、試劑組 ……………………………………………………12
三、酵素 ………………………………………………………12
四、抗體 ………………………………………………………13
五、細胞培養相關材料及抗生素 ………………………………13
六、實驗儀器 …………………………………………………15
七、其他材料 …………………………………………………15
第三章 實驗方法 …………………………………………………16
ㄧ、實驗藥品配置 ……………………………………………16
二、細胞培養 …………………………………………………16
三、分析CYP3A5短暫性轉染以及stable clone selection ……… 19
四、VDR-si-RNA短暫性轉染之分析 ……………………………………20
五、CYP3A4、VDR mRNA表現量分析 …………………………21
六、CYP3A4、CYP3A5蛋白質表現量分析 ………………………24
第四章 實驗結果 …………………………………………………29
ㄧ、Overexpression of CYP3A5對Caco-2細胞與HepG2細胞中
CYP3A4蛋白表現量的影響 ……………………………29
二、Estradiol (雌激素)不會影響CYP3A4的蛋白表現量 …………30
三、Overexpression of CYP3A5以及estradiol(雌激素)對Caco-2
細胞中CYP3A4蛋白表現量的影響 ………………………… 30
四、Overexpression of CYP3A5以及estradiol(雌激素)對HepG2
細胞中CYP3A4蛋白表現量的影響 ………………………… 31
五、Caco-2細胞中estradiol (雌激素)可能透過vitamin D
receptor(VDR)影響CYP3A4蛋白表現量 ……………………………31
六、HepG2細胞中estradiol (雌激素)可能不透過vitamin D
receptor(VDR)影響CYP3A4蛋白表現量 ……………………………32
七、Caco-2細胞中knock down VDR使CYP3A4 mRNA表現量回復 32
八、Caco-2細胞中knock down VDR使CYP3A4蛋白表現量回復… 33
第五章 結論與討論…………………………………………………34
一、結論 ………………………………………………………34
二、討論 ………………………………………………………35
參考文獻 ………………………………………………………… 44
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