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研究生:林家蓁
研究生(外文):Jia-jhen Lin
論文名稱:學名藥Danazol抑制黑色素細胞黑色素生合成之機轉研究
論文名稱(外文):Inhibitory effects of generic drug danazol on melanogenesis in mouse B16 melanoma cells
指導教授:張德生張德生引用關係
指導教授(外文):Te-sheng Chang
學位類別:碩士
校院名稱:國立臺南大學
系所名稱:生物科技學系碩士班
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:2011
畢業學年度:99
語文別:中文
論文頁數:65
中文關鍵詞:黑色素酪胺酸酶黑色素生成抑制劑
外文關鍵詞:MelaninTyrosinaseMelanogenesisDanazolInhibition
相關次數:
  • 被引用被引用:3
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本研究中,初步以斑馬魚(Danio rerio)活體模式篩選近百種臨床藥物之皮膚黑色素生成抑制能力,所篩得之學名藥danazol,則再進一步藉由老鼠B16黑色素瘤細胞研究其詳細之抑制黑色素生成之作用機轉。研究中,黑色素瘤細胞先經黑色素刺激荷爾蒙(α-melanocyte stimulating hormone, α-MSH)或胞內cAMP促進劑3-isobutyl-1-methylxanthin (IBMX)刺激後的黑色素生成抑制試驗之結果發現,danazol在老鼠B16黑色素瘤細胞具有劑量抑制效應的現象,且其半數抑制濃度為2.2 μM。此外,danazol在老鼠B16黑色素瘤細胞可降低細胞內之酪胺酸酶活性,但在試管試驗系統中卻無法直接抑制老鼠之酪胺酸酶活性。經西方墨點分析試驗結果顯示danazol在老鼠B16黑色素瘤細胞可低調節酪胺酸酶之蛋白量,而反轉錄聚合酶鏈反應(RT-PCR)結果發現danazol並不會低調節酪胺酸酶之mRNA量。另外,danazol對小鼠活體模式之皮膚美白效能分析,結果顯示其塗抹於小鼠皮膚具有美白的效果。從以上之研究結果顯示,danazol在老鼠B16黑色素瘤細胞中,主要是藉由後轉錄調節來降低酪胺酸酶之蛋白量,進一步降低細胞內酪胺酸酶的活性,最後抑制黑色素生成,其效果可從小鼠活體模式試驗結果進一步得到證實。本研究所得到之成果,已證實danazol之抑制機轉以及其在降低皮膚色素沉著方面可作為一個很有效用、有潛力之皮膚美白藥劑。
In the present study, we screened more than 100 generic drugs to verify their applicability as skin-lightening agents by using mouse B16 melanoma cells. Of these, danazol was found to inhibit melanogenesis in B16 cells in a dose-dependent manner with an IC50 value of 2.2 μM. In addition, danazol reduced cellular tyrosinase activity in B16 cells but not directly inhibited murine tyrosinase activity in the cell-free system. Applying a cream containing 0.4% danazol twice daily on the skin of mice also increased the skin-whitening index value after one week of treatment and the increase continued for another 30 days. Furthermore, western blotting analysis confirmed that danazol downregulated the level of tyrosinase protein in B16 cells, while reverse-transcription polymerase chain reaction (RT-PCR) analysis found that danazol did not downregulate the level of tyrosinase mRNA in the cells. These results demonstrated that danazol inhibits melanogenesis in B16 cells via reducing tyrosinase activity with a post-transcriptional regulation.
摘 要 i
Abstract ii
誌 謝 iii
目 錄 iv
圖 目 錄 vi
縮寫對照表 1
第1章 緒論 2
1.1 研究背景 2
1.2 研究目的 2
1.3 研究架構 3
第2章 文獻回顧 4
2.1 生物體內黑色素生成之機轉 4
2.1.1 前言 4
2.1.2 黑色素之生成途徑 6
2.1.3 Tyrosinase 8
2.2 抑制黑色素生成的調控機轉 9
2.2.1 前言 9
2.2.2 Tyrosinase活性抑制 11
2.2.3 抑制MITF生成與促進MITF之降解 12
2.2.4 抑制tyrosinase之合成 14
2.2.5 促進tyrosinase之降解 15
2.3 Danazol背景介紹 16
2.3.1 前言 16
2.3.2 雄性激素(Testosterone) 16
2.3.3 Danazol之應用與副作用 19
第3章 材料與方法 21
3.1 材料 21
3.1.1 藥品 21
3.1.2 Primers序列及訂購公司 22
3.1.3 溶液配製 23
3.1.4 儀器 26
3.1.5 斑馬魚活體 27
3.1.6 小鼠活體 27
3.1.7 細胞株來源 27
3.2 方法 28
3.2.1 斑馬魚胚胎之皮膚美白篩選分析 28
3.2.2 蛋白質含量測定 28
3.2.3 繼代細胞培養 28
3.2.4 細胞冷凍保存 29
3.2.5 細胞計數 29
3.2.6 細胞毒性測試(MTT法) 30
3.2.7 B16-F1細胞內黑色素含量測定 30
3.2.8 B16-F1細胞內tyrosinase活性測定 30
3.2.9 細胞外老鼠細胞tyrosinase活性抑制之測定 31
3.2.10 蛋白質電泳(SDS-PAGE) 32
3.2.11 西方墨點法(Western Blotting) 33
3.2.12 反轉錄聚合酶連鎖反應(RT-PCR) 34
3.2.13 小鼠活體之皮膚美白分析 35
3.2.14 統計分析 35
第4章 結果 36
4.1 以斑馬魚胚胎進行臨床藥物皮膚美白篩選 36
4.2 Danazol對老鼠B16細胞之毒性測試 37
4.3 Danazol對老鼠B16細胞黑色素生成之抑制測試 39
4.4 Danazol對tyrosinase活性的影響 43
4.5 Danazol對老鼠B16細胞內tyrosinase蛋白質含量和mRNA含量之影響 45
4.6 Danazol對小鼠活體之皮膚美白分析 46
第5章 討論 47
5.1 篩選學名藥具黑色素生成抑制活性 47
5.2 Danazol對老鼠B16黑色素腫瘤細胞之黑色素生成抑制試驗 48
5.3 Danazol對tyrosinase活性之影響 49
5.4 Danazol對小鼠活體之皮膚美白分析 50
5.5 Danazol抑制黑色素生成之機轉 51
第6章 結論與未來展望 52
6.1 結論 52
6.2 未來展望 52
第7章 參考文獻 53
附錄一 臨床藥物列表 61
附錄二 蛋白質標準曲線圖 63
附錄三 老鼠B16黑色素瘤細胞蛋白質含量圖 64
附錄四 黑色素標準曲線圖 65
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