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研究生:陳韻如
研究生(外文):Yun-Ru Chen
論文名稱:由天然漆中純化的烷基對苯二酚對於抑制酪胺酸酶及黑色素生成之研究
論文名稱(外文):Studies on an alkylhydroquinone from Rhus succedanea as an inhibitor of tyrosinase and melanogenesis
指導教授:林淑萍林淑萍引用關係
指導教授(外文):Shwu-Bin Lin
學位類別:博士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學研究所
學門:生命科學學門
學類:生物科技學類
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:141
中文關鍵詞:天然漆烷基對苯二酚酪胺酸酶抑制劑抑制黑色素生成美白
外文關鍵詞:Rhus succedaneaalkylhydroquinonetyrosinase inhibitoranti-melanogenesisskin whitening
相關次數:
  • 被引用被引用:1
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  • 收藏至我的研究室書目清單書目收藏:0
由於化妝品工業的發展,及東方人對於膚色白皙的追求,開發有效的美白成分已經成為一個重要的研究課題。人類皮膚中所分布的黑色素細胞數大致上是相同的,而造成不同人之間膚色上的差異,主要是因為真黑色素 (Eumelanin) 與深黑色素 (Pheaomelanin) 的比例不同、黑色素在角質細胞中分佈的情形、黑色素細胞中酪胺酸酶 (tyrosinase) 的活性及一些環境因素的影響。酪胺酸酶是一個結構複雜的含銅氧化還原酵素,廣泛的存在于微生物、動植物及人體中。酪胺酸酶的化學活性在於將多酚類 (polyphenol) 的化合物氧化。在生物體黑色素細胞中,酪胺酸酶會催化酪胺酸的氧化反應,進而生成黑色素及其他色素,而且酪胺酸酶的催化反應是色素生成的速率決定步驟,因此目前最常用來調控黑色素細胞中黑色素生成的方式是利用一些具有和酪胺酸結構相似的物質,使其可以和酪胺酸酶的酵素催化中心結合,競爭性的抑制酪胺酸酶的活性,進而抑制黑色素生成,以達到調整皮膚顏色的目的。在之前的研究中,我們已經由漆樹Rhus succedanea的漆液中萃取純化得到的一個對苯二酚衍生物,此衍生物在第二個碳的位置有17個碳的不飽和碳鏈,根據其化學結構命名為10′(Z) –heptadecenylhydroquinone,並簡稱為HQ17(1)。在本實驗中,我們發現HQ17(1)能夠有效的抑制酪胺酸酶的活性,在細胞中可以抑制黑色素的生成,並利用已知的酪胺酸酶及黑色素生成抑制劑 “對苯二酚” 作為正向對照組。HQ17(1)對於酪胺酸酶的半抑制濃度 (IC50) 為37 µM,而對苯二酚則需要到70 µM才會有50%的抑制效果。在B16老鼠黑色素瘤細胞實驗方面,HQ17(1)對於抑制黑色素生成的半有效濃度 (EC50) 為40 µM,而對苯二酚則需要124 µM才達到EC50,並且在以HQ17(1)處理細胞時,細胞內的活性氧自由基增加的情況並不嚴重,和以對苯二酚處理細胞時的明顯的不同。此外,我們也同時利用間斷性給藥的方式進一步的証明HQ17(1)能夠有效的抑制細胞內黑色素的生成。經由細胞內HQ17(1)分布情形的研究,我們推測HQ17(1)上的不飽和長碳鏈很可能會幫助HQ17(1)鑲嵌在細胞膜上及避免苯環的氧化,而酪胺酸酶是一個膜蛋白,這可以增加HQ17(1)和其反應的機會,因此可能是HQ17(1)有效抑制酪胺酸酶活性及黑色素生成很重要的原因。有鑒於酪胺酸酶是動物體內黑色素生成重要的關鍵酵素,而HQ17(1)卻可以有效的抑制酪胺酸酶的活性,因此我們認為HQ17(1)具有發展成為美白化妝品成分的潛力。在本篇研究中,我們同時也證明了以HQ17(1)處理細胞後,ERK訊息傳遞的路徑會被活化,進而會導致黑色素生成相關蛋白質的mRNA及細胞內酪胺酸酶蛋白質的含量降低。總而言之,HQ17(1)能夠利用兩種作用方式有效的抑制酪胺酸酶的活性及細胞黑色素的生成,因此我們認為HQ17(1)具有成為在化妝品及醫療上使用的酪胺酸酶抑制劑或抗黑色素生成藥劑。
The development of effective skin whitening agents has become an increasing important research area. Human have approximately the same number of melanocytes in the skin. Differences in skin color are primarily due to the ratio of eumelanin to pheomelanin, their distribution in keratinocytes, degree of tyrosinase activity in melanocyte, and environmental factors. Tyrosinase is a copper-containing oxidase that catalyses the oxidation of phenol like compounds (such as tyrosine) and is widespread in plants and animals. Tyrosinase catalyzes the production of melanin in mammals and other pigments from tyrosine by oxidation. Modulation of melanogenesis in the melanocytes can be achieved using chemicals that share structural homologies with the substrate tyrosine and as thus competitively inhibit the catalytic function of tyrosinase. In this study, alkylhydroquinone, 10''(Z)-heptadecenylhydroquinone [HQ17(1)], isolated from the sap of the lacquer tree Rhus succedanea, was found to inhibit the activity of tyrosinase and to suppress melanin production in animal cells. The IC50 of HQ17(1) as a tyrosinase inhibitor was 37 µM versus 70 µM for hydroquinone (HQ), a known inhibitor of tyrosinase and melanogenesis. For the inhibition of melanin production in mouse B16 melanoma cells, the EC50 of HQ17(1) was 40 µM versus 124 µM for HQ. HQ17(1) induced much less cellular reactive oxygen species (ROS) than did HQ. The effectiveness in inhibiting melanin production could be mimicked by intermittent exposure of cells to HQ17(1). The potent inhibitory effects of HQ17(1) on tyrosinase activity and melanin production are likely due to its heptadecenyl chain, which facilitates retention of the compound in cell membrane compartments and may impedes the oxidation of the hydroquinone ring. As tyrosinase activity accounts for the melanogenesis in animal skin, HQ17(1) could be useful in skin whitening cosmetics. In this study, we had also demonstrated that HQ17(1) can suppress the mRNA expression of melanogenesisi related genes and the cellular protein level of tyrosinase. This decreasing effect may due to the activation of ERK pathway by HQ17(1) induction. Taken together, HQ17(1) can inhibit the synthesis of melanin via a dual-action mechanism suggesting that HQ17(1) had the potential to become a useful tyrosinase inhibitor or anti-melanogensis agent in cosmetics and medicine.
目錄
口試委員審定書 --------------------------------------------------------------------------------i
致謝 ----------------------------------------------------------------------------------------ii
中文摘要 ----------------------------------------------------------------------------------------iii
英文摘要 ----------------------------------------------------------------------------------------v
縮寫表 ----------------------------------------------------------------------------------------vii
第一章. 序論 -----------------------------------------------------------------------------------------1
1.1 酪胺酸酶 (Tyrosinase) ---------------------------------------------------------------------1
1.2 酪胺酸酶相關蛋白 -------------------------------------------------------------------4
1.3 黑色素細胞 (Melanocyte) ----------------------------------------------------------------5
1.4 黑色素 (Melanin) -------------------------------------------------------------------------10
1.5 黑色素生成的訊息傳遞路徑 -------------------------------------------------------------------13
1.6 抑制黑色素生成的機制 -----------------------------------------------------------------------15
1.7 對苯二酚 (HQ) 之相關研究-----------------------------------------------------------------20
1.8 純化自漆樹的烷基對苯二酚 (alkylhydroquinone) --------------------------------------22
1.9 酵素動力學 (Enzyme kinetics) --------------------------------------------------25
1.10 Vmax 及 Km 的測定與意義--------------------------------------------------------------28
1.11 酵素活性的抑制之反應形態----------------------------------------------------------29
1.12 活性氧自由基 (ROS, Reactive oxygen species) -------------------------------------33
1.13 粒線體膜電位 (Mitochondria membrane potential) -------------------------35
1.14 N-乙醯基半胱胺酸 (N-acetylcysteine) -------------------------------------------37
1.15 研究目的及實驗流程 -------------------------------------------------------------------------39
第二章. 材料與方法 ------------------------------------------------------------------------------40
2.1 實驗使用的藥品及抗體列於附錄 -------------------------------------------------------------40
2.2 由天然漆中純化HQ17(1) ------------------------------------------------------------------------40
2.3 細胞培養 -------------------------------------------------------------------------------------------41
2.4 細胞活性測定 -------------------------------------------------------------------------------------42
2.5 細胞蛋白質萃取 ----------------------------------------------------------------------------------42
2.6 酪胺酸酶活性測定 -------------------------------------------------------------------------------43
2.7 黑色素生成的測定 -------------------------------------------------------------------------------43
2.8 測定HQ17(1)在細胞膜及細胞質的分佈情形----------------------------------------44
2.9 細胞內ROS的測定 ------------------------------------------------------------------------------45
2.10 細胞粒線體膜電位的測定 ----------------------------------------------------------------------45
2.11 細胞膜完整性的測定 ----------------------------------------------------------------------------46
2.12 核糖核酸的萃取 ----------------------------------------------------------------------------------46
2.13 反轉錄-聚合酵素連鎖反應 ---------------------------------------------------------------------47
2.14 西方墨點法 ----------------------------------------------------------------------------------------48

第三章. 結果 -----------------------------------------------------------------------------------------------49
3.1 由天然漆中純化HQ17(1) ------------------------------------------------------------------------49
3.2 HQ17(1)為酪胺酸酶的抑制劑 -----------------------------------------------------------------49
3.3 HQ17(1)能夠抑制黑色素細胞中酪胺酸酶的活性及黑色素的生成 -------------50
3.4 HQ17(1)進入細胞後易滯留於細胞膜 -------------------------------------------------------52
3.5 抗氧化劑NAC能有效的促進HQ17(1)抑制黑色素生成的作用 ------------------54
3.6 HQ17(1)抑制黑色素生成相關分子基因的表現並阻斷黑色素生成之訊息傳遞路徑 -------------------------------------------------------------------------------------------------------55
3.7 HQ17(1)對於細胞毒性極低 --------------------------------------------------------------------56
3.8 HQ17(1)對於細胞毒性的影響無法經由給予NAC而恢復 --------------------------57
3.9 HQ17(1)不會造成細胞的氧化傷害但對細胞膜的完整性有些微的影響 ------58
第四章. 結論與討論 ---------------------------------------------------------------------------60
第五章. 未來展望 ---------------------------------------------------------------------------64
5.1 鑒定HQ17(1)的性質 ---------------------------------------------------------------------64
5.2 HQ17(1)用於化妝品的安全性評估 -------------------------------------------------------64
5.3 HQ17(1)的複方成分對於黑色素生成的影響 ------------------------------66
5.4 以動物模式研究HQ17(1)對於黑色素生成的影響 ---------------------------------67
5.5 HQ17(1)對於細胞內訊息傳遞的影響 ------------------------------------------------------68
第六章. 參考文獻 ---------------------------------------------------------------------------99
附錄一. 藥品清單 --------------------------------------------------------------------------------112
附錄二. 細胞活性測定 -------------------------------------------------------------------116
附錄三. 以BCA kit測定蛋白質濃度 -----------------------------------------------117
附錄四. DCFDA染色測定細胞內ROS的含量 ---------------------------------------119
附錄五. 反轉錄-聚合酵素連鎖反應 -------------------------------------------------------------120
附錄六. 西方墨點法的詳細步驟 ------------------------------------------------------------------122
附錄七. HQ17(1)安全性評估的實驗方法 --------------------------------------------126
附錄八. 目前使用於美白化妝品的化合物種類 --------------------------------------------130
附錄九. 膚色的測量 -----------------------------------------------------------------------------------131
已發表之論文 -------------------------------------------------------------------------------------132
個人履歷表 -------------------------------------------------------------------------------------------138
相關著作 -------------------------------------------------------------------------------------------------139
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