臺灣博碩士論文加值系統

紫外線照射會導致許多皮膚疾病，且長期暴露於紫外線中亦會造成皮膚細胞之損傷。近年來，使用植物萃取物當作抗紫外線之成分儼然已蔚為風潮。原兒茶酸(PCA)富含於蔬菜水果等食物中，具抗氧化之功效，並且於體外試驗及活體試驗中證實其具有預防癌症生成及抑制腫瘤細胞生長之功效。然而，針對PCA對美容保健之化學預防活性的研究甚少。於本研究中，欲探討PCA抗紫外線引起皮膚皺紋及黑色素生成之研究。其結果顯示，於不產生細胞毒性濃度下的PCA具有抑制人類角質細胞株(HaCaT)受紫外線促進黑色素生成之功效。於即時定量PCR及西方墨點法實驗中證實，PCA抑制黑色素生成機制起始因子p53及POMC的表現量而抑制黑色素生成。本實驗也證明PCA得以抑制UV照射A375細胞後誘發之MC1-R表現量，進而抑制誘發黑色素生成因子與受器結合，細胞質中的MITF亦會受到PCA影響，使其降低轉錄進入細胞核內，最終導致生成黑色素之關鍵蛋白TRP-1及TRP-2的含量受到抑制，達到減緩黑色素生成之功效。PCA亦可抑制WS1細胞受到UVB誘發之基質金屬蛋白酶(MMP)含量，並增加前-膠原蛋白(Pro-collage)的含量，進而達到抗皺之功效。結果顯示，PCA得以阻斷UVB誘導之p53/POMC訊息路徑及MMP生成，與黑色素生成及皺紋的形成具相關性。總而言之， PCA或許得以開發成新的具有化學預防活性之美容保健產品。

Ultraviolet radiation (UV) is the cause of many skin diseases, and UV exposing on long-time could cause the injury of skin cells. The use of phytonutrient as anti-UV agents has gained considerable importance in recent years. Protocatechuic acid (PCA) is discussed to represent antioxidative food components in a human diet rich in fruits and vegetables, and has been shown to prevent carcinogenesis or antitumor growth in vivo and in vitro. However, the studies involved in chemopreventive activity of beauty and health care of PCA are poorly few. In this study investigations were conducted to examine the mechanisms of the anti-UVB activity of PCA. Thus, this research will be investigated that the chemopreventive activities, including whitening and anti-wrinkle, of PCA and its molecular mechanisms. The results of melanin content assay revealed that PCA inhibited UVB-promoted melanogenesis of human HaCaT keratinocytes under non-cytotoxic concentrations. The PCA-inhibited Initiation Factor melanin formation mechanism and induction appeared to be a consequence of p53 and pro-opiomelanocortin (POMC) inactivation measured by real time-PCR and Western blotting. This experiment also proved to inhibit the UV irradiation PCA A375 cells show induced amount of MC1-R and inhibit melanin production induced by receptor binding factor,and then cytoplasm of the MITF PCA will also be affected, to reduce transcription to enter the nucleus, and ultimately lead to the generation of melanin of the key protein TRP-1 and TRP-2 levels was inhibited, the effect to slow down melanin production. Furthermore, the UVB-induced an increased expression of matrix metalloproteinase (MMP) and pro-collage were reversed by the treatment of PCA in WS1 cells. Our data imply that PCA treatment led to the blockage of UVB-induced p53/POMC signaling and MMP production was related to melanogenesis and wrinkle formation, respectively. All these results suggested that PCA may be useful to develop a new chemopreventive agent in beauty and health care.

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謝 誌 .............................................I
中文摘要 ...........................................IV
英文摘要 ...........................................VI
目 錄 .............................................XI
圖 目 錄 ..........................................XII
第 一 章 緒論 .......................................1
第 二 章 文獻整理 ...................................3
2.1 人體皮膚結構與功能 ..............................3
2.1.1 表皮層 .......................................3
2.1.2 真皮層 .......................................4
2.1.3 皮下組織 ....................................5
2.2 紫外線對皮膚的影響 ..............................5
2.3 短期紫外線對皮膚的影響 ...........................7
2.3.1 紅斑反應(erythema) ...........................7
2.3.2 色素沉澱(pigmentation) .......................7
2.3.3 皮膚組織的改變 ................................7
2.3.4 免疫抑制 .....................................8
2.4 長期紫外線對皮膚的影響 ...........................9
2.4.1 皮膚光老化(skin photoaging) ..................9
2.4.1.1 基質金屬蛋白酶之介紹 ........................11
2.4.1.2 基質金屬蛋白酶對皮膚光老化之調控 ..............13
2.4.2 皮膚光癌化(photocarcinogenesis) ..............13
2.5 紫外線對皮膚細胞外間質之影響 .....................14
2.5.1 細胞外間質(Extracellular matrix) .............14
2.6 紫外線對膠原纖維之影響 ...........................15
2.7 紫外線對彈性纖維之影響 ...........................16
2.8 紫外線對於葡萄糖胺聚合醣之影響 ....................17
2.9 紫外線照射引發黑色素生合成 .......................17
2.10 黑色素的生成及調節 .............................19
2.10.1 黑色素生成(Melanogenesis)之機轉 ..............20
2.10.2 黑色素體的形成及轉移 ..........................22
2.10.3 黑色素的調控機制 .............................22
2.11 洛神葵之背景介紹 ...............................28
2.11.1 洛神花之產地與型態 ...........................28
2.11.2 洛神花之性狀與已知成分 ........................29
2.12 原兒茶酸(protocatechuic acid，PCA) ............30
第 三 章 實驗架構 ...................................32
第 四 章 實驗材料與方法 ..............................34
4.1 實驗儀器與實驗藥品 ..............................34
4.1.1 實驗儀器設備 .................................34
4.1.2 實驗藥品試劑 .................................36
4.2 實驗細胞株來源及培養基配 .........................39
4.2.1 細胞株培養基配製 ..............................39
4.2.2 細胞培養 .....................................40
4.2.3 冷凍細胞 .....................................40
4.2.4 解凍細胞 .....................................41
4.3 實驗方法 .......................................41
4.3.1 細胞數之計數 ..................................41
4.3.2 細胞毒性試驗 ..................................42
4.3.3 紫外線B對於HaCaT、A375及WS1細胞株之傷害 .........43
4.3.4 不同濃度之原兒茶酸對於紫外線B曝照HaCaT、A375及
WS1細胞株之傷害(曝照後給藥) ....................43
4.3.5 流式細胞儀 ....................................44
4.3.6 Tyrosine hydroxylase 活性試驗 .................45
4.3.7 細胞內黑色素含量試驗 ...........................46
4.3.8 HaCaT、A375及WS1細胞蛋白質萃取 .................48
4.3.9 西方墨點法(Western Blotting) ..................48
4.3.9.1 蛋白質標準品檢量線製作 ........................48
4.3.9.2 樣本處理 ...................................48
4.3.9.3 鑄膠(SDS-PAGE) .............................49
4.3.9.4 電泳(electrophoresis) ......................49
4.3.9.5 轉漬(Transfer) .............................50
4.3.9.6 免疫墨點法(Immunoblot) ......................50
4.3.10 Gelatin/Casein zymography試驗 ...............51
4.3.11 酪胺酸酶活性膠體分析(Tyrosinase zymography) ...51
4.3.12 HaCaT、A375及WS1細胞RNA萃取 ..................52
4.3.13 轉cDNA ......................................53
4.3.14 即時定量聚合酶鏈反應 ..........................53
4.3.15 膠體電泳位移分析法(EMSA) ......................54
4.3.15.1 DNA probe製備 .............................54
4.3.15.2 鑄膠(Negative-TBE PAGE) ...................54
4.3.15.3 樣品處理 ...................................54
4.3.15.4 電泳(electrophoresis) .....................55
4.3.15.5 轉漬(Transfer) ............................54
4.3.15.6 免疫墨點法(Immunoblot) .....................56
第 五 章 實驗結果 ....................................57
第 六 章 討論與結論 ..................................71
參 考 文 獻 .........................................78
圖 表 ..............................................94
附 圖 ..............................................118

中文文獻
吳侑軒(2004)。靜宜大學化妝品科學系碩士論文。液態黑納豆對於皮膚保健之研究 。台中。台灣。
呂易珍(2004)。靜宜大學化妝品科學系碩士論文。液態納豆應用於化妝品之研究。台中。台灣。
李仰川(1999) 。美白化妝品，化妝品學原理。文京圖書有限公司。p.127-140.
李建雄(1992)。生物化學。藝軒圖書出版社。p.670-675。
林建興(2003)。國立台灣海洋大學食品科學系碩士論文。卻老去皺面膏複方藥材萃取物之抗氧化與保護纖維母細胞抗紫外線之效果
。基隆。台灣。
施曉婷(2004)。中山醫學大學營養科學研究所碩士論文。探討甲型硫辛酸對B16-F1黑色素瘤細胞中eumelanin生合成相關基因表
現之影響。台中。台灣。
范元鵠(2006)。國立台灣海洋大學碩士論文。川芎、細辛、白朮及杏仁萃取物之美白與抗老化效果與含此等萃取物之化妝品的
有效性。基隆。台灣。
唐郁評(2009)。國立成功大學生命科學系碩士論文。探討香椿萃取物抑制黑色素生成之分子機制。台南。台灣。
黃琬玲(2004)。國立中興大學畜產學系碩士論文。烏骨雞黑色素應用於防曬劑之研究。台中。台灣。
黃慧怡(2009)。靜宜大學化妝品科學系碩士論文。液態納豆對於纖維母細胞和黑色素腫瘤細胞紫外線防禦與黑色素生成影響之研究
。台中。台灣。
湯成杰(2005)。中山醫學大學生物科技系碩士論文。洛神花各成分萃取物對黑色素細胞瘤黑色素生成之影響。台中。台灣。
鄒珮珊(2004)。全球生技業搶搭千億化妝品市場-生技美容締造BIO美麗新世界。 生技時代，24，p16-26。
劉承煌(1991)。皮膚病理生理學。中國醫藥科技出版社。北京，p74-98。
薛煜彬(2008)。亞洲大學生物科技學系碩士論文。葡萄與葡萄細胞乙醇萃取物對抑制酪胺酸酶活性之效能評估。台中。台灣。
謝詠筌(2007)。南台科技大學生物科技研究所碩士論文。建立真菌材料於化妝品之功效篩選技術。台南。台灣。
嚴嘉蕙(2001)。化粧品概論。新文京開發出版有限公司。

網路資料
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http://www.bioweb.com.tw/feature_content.asp?ISSID=346&chkey1=美容&chkey2=化妝品&chkey3=&chkey4=&chkey5=

英文文獻
Abamba, G. (1993). Poucher’s perfumes, Cosmetics and Soaps, Vol. 3,Butler, H. (Eds.), Chapman & Hall
Publish, London, 9th ed. p.336-339.
Abbott, C., Jackson, I. J., Carritt, B. and Povey, S. (1991). The human homolog of the mouse brown gene
maps to the short arm of chromosome 9 and extends the known region of homology with mouse chromosome
4. Genomics 11, 471-3.
Ahn SJ, Koketsu M, Ishihara H, et al. (2006). Regulation of melanin synthesis by selenium-containing
carbohydrates. Chem Pharm Bull. 54(3):281-286.
Allen, J. B. (2001). Molecular mechanisms of aging in connective tissues. Mech. Aging Dev. 122: 735-
755.
Alley M. C. (1988). Feasibility of drug screening with panels of human tumor cell lines using a
microculture tetrazolium assay. Cancer Res. 48, 589-592.
Ando, H.; Funasaka, Y.; Oka, M.; Ohashi, A.; Furumura, M.; Matsunaga, J.; Matsunaga, N.; Hearing, V.J.;
Ichihashi, M. (1999). Possible involvement of proteolytic degradation of tyrosinase in the
regulatory effect of fatty acids on melanogenesis. J. Lipid Res. 40, 1312-1316.
Aroca, P., J. C.Garcia-Borron and F. Solano. (1990). Regulation of mammalian melanogenesis. I. Partial
purification and characterization of a dopachrome converting factor: dopachrome tautomerase.
Biochim. Biophy. Acta 1035: 266-275.
Ashok Chakraborty, Andrzej Slominski, Gennady Ermak, Jim Hwang and John Pawelek. J Invest Dermatol 105:
655-659.
Bajpai P., Agrawal P. K., Vishwanathan L., (1982). “Kojic acid:Synthesis and properties”, J. Sci.
Indust. Res., 41, pp.185-194.
Balaban et al. (1988). Basic fibroblast growth factor from human keratinocytes is a natural mitogen for
melanocytes. J Cell Biol. 107(4):1611-9.
Berneburg M., Plettenberg H., Krutmann J. (2000). Photoaging of human skin.Photodermatol Photoimmunol
Photomed. 16 : 239-244.
Birkedal-Hansen, H. (1987). Catabolism and turnover of collagens: collagenases. Methods Enzymol. 144
140-171.
Boissy, R. E., C. Skai and H. Zhao. (1998). Human tyrosinase related protein TRP-1 does not function as
a DHICA oxidase activity in contrast to murine TRP-1. Exp. Dermatol. 7: 198-204.
Bolognia, J. L. and S. J. Orlow. (2003). Melanocyte biology. In: Dermatology, (Eds J. L. Bolognia, J.
L. Jorizzo and R. P. Rapini ). Mosby: London, Edinburgh, New York, Philadelphia, St. Louis,
Sydney, Toronto. p.43-52.
Bolognia, J., Murray, M., Pawelek, J. (1989). UVB-induced melanogenesis may be mediated through the MSH- receptor system. J Invest Dermatol. 92(5), 651-6.
Brenneisen, P., J. Oh, M. Wlaschek, J. Wenk, K. Briviba, C. Hommel, G. Herrmann, H. Sies and K.
Scharffetter-Kochanek. (1996). Ultraviolet B wavelength dependence for the regulation of two major
matrix metalloproteinases and their inhibitor TIMP-1 in human dermal fibroblasts. Photochem.
Photobiol. 64: 649-657.
Byorksten, J. A. (1958). A common molecular basis for the aging syndrome. Journal of the American Geriatrics
Society. 6: 740.
Chakraborty, A. K., G. Slominski, G. Erinak, J. Hwang and J. Pawelek.(1995). Ultraviolet B and melanocyte
stimulating hormone simulate mRNA production for alpha MSH receptors and propiomelanocortin-derived
peptides in mouse melanoma cells and transformed keratinocytes. J. Invest. Dermatol. 105: 655-659.
Chakraborty, A.K., Funasaka, Y., Slominski, A., Ermak, G., Hwang, J.,Pawelek, J.M., and Ichihashi, M.
(1996). Production and release of proopiomelanocortin (POMC) derived peptides by human melanocytes and
keratinocytes in culture: regulation by ultraviolet B. Biochim. Biophys. Acta 1313, 130-138.
Cooksey, C., P. J. Garat, S. Pavel, E. J. Land, C. A. Ramsden, P. A. Riley and N. P. Smit. (1997). Evidence
of the indirect formation of the catecholic intermediate substrate responsible for the autoactivation
kinetics of tyrosinase. J. Biol. Chem. 272: 26226-26235.
D’Orazio, J.A., Nobuhisa, T., Cui, R., Arya, M., Spry, M.,Wakamatsu,K., Igras, V., Kunisada, T., Granter,
S.R., Nishimura, E.K., et al.(2006). Topical drug rescue strategy and skin protection based on the role
of Mc1r in UV-induced tanning. Nature 443, 340-344.
Damian, U. L., R. S. C. Barnetson and G. M. Halliday. (1999). Low-dose UVA and UVB have different time
courses for suppression of contact hypersensitivity to a recall antigen in humans. J. Invest. Dermatol.
112: 939-944.
David J. Gawkrodger 原著，曾銘儀 編譯(2004)，彩色圖解皮膚學，合記
Denhardt, D. T., B. Feng, D. R. Edwards, E. T. Cocuzzi and U. M. Malyankar. (1993). Tissue inhibitor of
metalloproteinases (TIMP): structure, control of expression and biological functions. Pharmacol.
Ther. 59: 329-341.
Duggan M. Wilmott J., Znalden A. (1987). Tyrosinase-The Enzyme Behind the Tan, Cosm. Toil. 102, 97-101.
Eller, M.S., Ostrom, A., and Gilchrest, B.A. (1996). DNA damage enhances melanogenesis. Proc. Natl. Acad.
Sci. USA 93, 1087-1092.
Eller, M.S., Yaar, M., and Gilchrest, B.A. (1994). DNA damage and melanogenesis. Nature 372, 413-414.
Elmets, C. A., P. R. Bergstresser, R. E. Tigelaar, P. J. Wood and J. W. Streilein. (1983). Analysis of the
mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet
radiation. J. Exp. Med. 158: 781-794.
Epstein, J. H., K. Fukuyama, and K. Fye. (1970). Effects of ultraviolet radiation on the mitotic cycle and
DNA, RNA and protein synthesis in mammalian epidermis in vivo. Photochem. Photobiol. 12: 57-65.
Eric, F. B. and Jouni, U. (1996). The effect of photodamage on dermal extracellular matrix. Clinical
Dermatology. 14: 143-151.
Feingold (1990).Gender differences in effects of physical attractiveness on romantic attraction: A
comparison across five research paradigms. Journal of Personality and Social Psychology,59(5), 981-993.
Fisher, G. J., S. Datta, S. Talwar, Z. Wang, J. Varani, S. Kang and J. J. Voorhees. (1996). Molecular basis
of sun-induced premature skin ageing and retinoid antagonism. Nature 379: 335-339.
Friedmann, P.S., and Gilchrest, B.A. (1987). Ultraviolet radiation directly induces pigment production by
cultured human melanocytes. J. Cell. Physiol. 133, 88-94.
Furumura, M., C. Sakai, Z. Abdel-Malek, G. S. Barsh. and V. J. Hearing.(1996). The interaction of agouti
signal protein and melanocyte stimulating hormone to regulate melanin formation in mammals.Pigment Cell
Res. 9: 191-203.
Gary J., Zeng Quan Wang, Subhash C. Datta, James Varani, Sewon Kang and John J. Voorhees. (1997).
Pathophysiology of premature skin aging induced by ultraviolet light. The New England Journal of
Medicine. 337(20):1419-1428.
Genji, I., Yoshinori, T., Yukiko, Y., Kazue, T., Michio, K. and Shuhei, I.(1995). Degree of elastic fibers
in rat skin is age dependent. J. Invest. Dermatology. 2: 254-258 .
Gibbbs et al. (2000). Epidermal growth factor and keratinocyte growth factor differentially regulate
epidermal migration, growth, and differentiation. Wound Repair Regen. 8(3) :192-203.
Gilchrest, B. A, H. Y. Park, M. S. Eller and M. Yaar. (1996). Mechanisms of ultraviolet-induced
pigmentation. Photochem. Photobiol. 63:1-10.
Glogau, R. G. (1997). Physiologic and structural changes associated with aging skin. Dermatol. Clin. 15: 555-
559.
Golgsmith L.A. (1983). Biochemistry and Physiology of the skin,Oxford University Press, Inc., New York ,109:
59-64.
Grossman, D. and D. J. Leffel. (1997). The molecular basis of nonmelanoma cancer. New understanding. Arch.
Dermatol. 133: 1263-1270.
Hachiya A, Kobayashi T, Takema Y, Imokawa G. (2002).Biochemical characterization of endothelin-converting
enzyme-1alpha in cultured skin-derived cells and its postulated role in the stimulation of melano-
genesis in human epidermis. J Biol Chem.15;277(7) :5395-5403.
Hall, P. A., P. H. McKee, H. D. Menage, A. Dove and D. P. Lane. (1993). High levels of p53 protein in UV-
irradiated normal human skin. Oncogene 8: 203-207.
Hawk, J. L., G. M. Murphy and C.A. Holden. (1988). The presence of neutrophils in human cutaneous
ultraviolet-B inflammation. Br. J. Dermatol. 118: 27-30.
Hersey, P., E. Has, A. Edwards, V. Bradley, G. Horan and W. H. McCarthy. (1983). Immunological effects of
solarium exposure. Lancet 1: 545-548.
Hideya Ando, Hirofumi Kondoh, Masamitsu Ichihashiand Vincent J. Hearing.(2007) Approaches to Identify
Inhibitors of Melanin Biosynthesisvia the Quality Control of Tyrosinase. Journal of
Investigative Dermatology.127: 751-761.
Hiramoto, K., Ojima, N., Saito, K., and Kikugawa, K. (1996). Effect of plant phenolics on the formation of
the spin-adduct of hydroxyl radical and the DNA strand breaking by hydroxyl radical. Biol Pharm
Bull. 19:558-563.
Hiroaki, K., Masahiro, Y., Yuki, O., Koji, T., Yoko, F. and Masamitsu I. (2001). Epidermal change caused by
chronic low-dose UV irradiation induce wrinkle formation in hairless mouse. J. Dermatol. Sci.1:19-25.
Hirose Y, Tanaka T, Kawamori T, Ohnishi M, Makita H, Mori H,. Satoh K, Hara A (1995). Chemoprevention of
urinary bladder carcinogenesis by the natural phenolic compound protocatechuic acid in rats.
Carcinogenesis 16:2337-2342.
Hung M, Ferraro T. Phenolic compounds in food and cancer prevention. In Huang MT, Ho CT, Lee CY. (eds).
(1992). Phenolic compounds in Food and Their Effects on Health H: Antioxidants and Cancer prevention.
American Chemical Society Symposium Series 507, American Chemical Society, Washington, DC, p8-34.
Ichiro, K., Emina, H., Hiroaki, M. and Toshio, I. (1999). Quantitative alterations of hyaluronan and
dermatan sulfate in the hairless mouse dorsal skin exposed to chronic UV irradiation. Biochem. 1428:
327-333.
Im, S., Mori, O., Peng, F., Medrano, E.E., Cornelius, J., Babcock, G., Nordlund, J.J., and Abdel-Malek, Z.A.
(1998). Activation of the cyclic AMP pathway by alpha-melanotropin mediates the response of human
melanocytes to ultraviolet B radiation. Cancer Res. 58:47-54.
Imokawa, G. (2004). Autocrine and paracrine regulation of melanocytes in human skin and in pigmentary
disorders. Pigment Cell Res.17:96-110.
Jackson, J., Chambers, M., Tsukamoto, K., Copeland, N.G., Gilbert, D. J.,Jenkins, N. A. and Hearing, V.
(1992). Asecond tyrosinase-related protein, TRP-2, maps to and is mutated at the mouse slaty locus.
Embo. J.11:527-35.
Jimbow, Kowichi. (1995). Current update and trends in melanin pigmentation and melanin biology. Keio J Med.
Mar ; 44(1) :9-18.
Kaidbey, K. H., M. S. Poh-Again, R. M. Sayre and A. M. Kligman. (1979). Photo-protection by melanin: a c
omparison of black and Caucasian skin. J. Am. Acad. Dermatol. 1: 249-260.
Kawaguchi, Y., Tanaka, H., Okada, Y., Konishi, H., Takahashi, M., Ito, M. and Asai, J. (1997). Effect of
reactive oxygen species on the elastin mRNA expression in cultured human dermal fibroblasts. Free Radic.
Biol. Med. 23(1): 162-165.
Kawamori T, Tanaka T, Kojima T, et al. (1994). Suppression of azoxymethane-induced rat colon aberrant crypt
focal by dietary protocatechuic acid. Jpn J Cancer Res:85: 686.
Kawamori T, Tanaka T, Kojima T, Suzui M, Ohnishi M, Mori H. (1994).Suppression of azoxymethyane-induced rat
colon aberrant crypt foci by dietary protocatechuic acid. Jpn. J. Cancer Res. 85: 691-696.
Kazuomi. Sato , Masaru. Toriyama. (2009). Effect of pyrroloquinoline quinone (PQQ) on melanogenic protein
expression in murine B16 melanoma. Journal of Dermatological Science, 53:140-145.
Kielbassa, C., L. Roza and B. Epe. (1997). Wavelength dependence of oxidative DNA damage induced by UV and
visible light. Carcinogenesis 18: 811-816.
Kim, H. H., Lee, M. J., Lee, S. R., Kim, Y. H., Cho, K. H., Eun, H. C., Chung, J. H. (2005). Augmentation of
UV-induced skin wrinkling by infrared irradiation in hairless mice. Mechanisms of Ageing and Development.
126: 1170-1177.
Kobayashi, T., Imokawa, G., Bennett, D. C. and Hearing, V. J. (1998). Tyrosinase stabilization by Tyrp1 (the
brown locus protein). J. Biol. Chem. 273:31801-5.
Kobayashi, T., Urabe, K., Winder, A., Jimenez-Cervantes, C.,Imokawa, G., Brewington, T., Solano, F., Garcia-
Borron, J. C.and Hearing, V. J. (1994).Tyrosinase related protein 1 (TRP1) functions as a DHICA oxidase
in melanin biosynthesis. Embo.J. 13:5818-5825.
Kobayashi, T., Urabe, K., Winter, A. (1991). Oxidase activity of TRP-1 and interaction with other
melanogenic enzymes. Pigment Cell Res. 7:227-234.
Kochevar, I. E. (1995). Molecular and cellular effects of UV radiation relevant to chronic photodamage. In
Photodamage (Bilchrest, B.A.,ed.), p.51-58, Blackwell Science, MA.
Krishna,. (1975), Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining.
J. Cell Biol. July 1; 66(1): 188-193.
Kuzumaki, T., Matsuda, A., Wakamatsu, K., Ito, S. and Ishikawa, K. (1993). Eumelanin biosynthesis is
regulated by coordinate expression of tyrosinase and tyrosinase-related protein-1 genes. Exp. Cell. Res.
207:33-40.
Lane, D.P. (1992). p53, guardian of the genome. Nature 358: 15-16.
Latt S. A., Allen J., Bloom S. E., Carano A. V. Falke E., Kram D. (1981). “Sister chromatid exchange: a
report of the GENE-TOX program”, Mutat. Res., 87, pp.17-62,
Lavker, R. M., D. A. Veres, J. Irwin and K. H. (1995). Quantitative assessment of cumulative damage from
repetitive exposures to suberythemogenic doses of UVA in human skin. Photochem. Photobiol. 62: 348-352.
Liu YT, Su MI, Ji DI, Wu YH, Chou CC, Chen CC. (1993). Protection from ultraviolet irradiation by melanin of
mosquitocidal activity of Bacillus thuringiensis var. israelensis. J Invertebr Pathol. 62(2):131-6.
Luger, T. A., T. Scholzen and S.Grabbe. (1997). The role of α-melanocyte- stimulating hormone in cutaneous
biology. J. Invest. Dermatol.Symp. Proc. 2: 87-93.
Management of the Older Person With Atrial Fibrillation. Special Series. Journal of the American Geriatrics
Society. 47(6):740-748.
Marieb, E. N. (1989). Human anatomy and physiology. The Benjamin/Gummings Publishing Company, California.
Marmol, V., Ito, S., Jackson, I., Vachtenheim, J., Berr, P., Ghanem, G., Morandini, R., Wakamatsu, K. and
Huez, G. (1993). TRP-1 expression correlates with eumelanogenesis in human pigment cells in culture. FEBS
Lett. 327: 307-10.
Matsumura Y, Ananthaswamy H.N. (2004). Toxic effects of ultraviolet radiation on the skin. Toxicology and
Applied Pharmacology. 195: 298-308.
McGregor, J. M. and J. L. Hawk. (1999). Acute effects on ultraviolet radiation on the skin. In Dermatology
in General Medicine (Freedberg, I. M. et al., eds). p.1555-1561.
Meanwell, E. F. and B. L. Diffey. (1989). Reciprocity of ultraviolet erythema in human skin. Photodermatol.
6: 146-148.
Menter, J. M., L. M. Cornelison, L. Cannick, A. M. Patta, J. C. Dowdy, R. M. Sayre, I. K. Abukhalaf, N. S.
Silvestrov and Willis. I. (2003). Effect of UV on the susceptibility of acid-soluble Skh-1 hairless
mouse collagen to collagenase. Photodermatol. Photoimmunol. Photomed. 19: 28-34.
Mossman, T. (1983). Methods of MTT assay. J. Immunol. 65: 55-63.
Mutation in and lack of expression of tyrosinase-related protein-1(TRP-1) in melanocytes from an individual
with brown oculocutaneous albinism: a new subtype of albinism classified as ”OCA3”. Am. J. Hum. Genet.
58, 1145-56.
Nakamura T, Nakazawa Y, Onizuka ST, et al. (1995). Antimutagenicity of Tochu tea (an aqueous extract of
Eucommia ulmoides leaves). The clastogen-suppressing effects of Tochu tea in CHO cells and mice.
Mutat Res: 388: 7.
Nicholas, J. L., David, P. M., Joshua, M. W., Debra, L., Teresa, B., Marjorie, D. L., Anthony, W. J. and
Ian, R. S. (1995). Low doses of repetitive ultraviolet A induce morphologic changes in human skin. J.
Invest. Dermatol. 6: 739-743.
Nomura A. M. Y., Kolonel LN, Hankin JH, Yoshizawa CN. (1991). Dietary factors in cancer of the lower urinary
trace. Int J Cancer. 48:199.
Nomura, T., H. Nakajima, T. Hongyom. (1997). Inductions of cancer, actinic keratosis, and specific p53
mutations by UVB light in human skin maintained in severe combined immunodeficient mice. Cancer
Res. 57: 2081-2084.
Onoue, S., Kobayashi, T., Takemoto, Y., Sasaki, I., Shinkai, H. (2003). Induction of matrix
metalloproteinase-9 secretion from human keratinocytes in culture by ultraviolet B irradiation. Journal
of Dermatological Science. 33: 105-111.
Orlow, S. J., Zhou, B. K., Chakraborty, A. K., Drucker, M., Pifko-Hirst, S. and Pawelek, J. M. (1994). High-
molecular-weight forms of tyrosinase and the tyrosinase-related proteins: evidence for a melanogenic
complex. J. Invest. Dermatol. 103: 196-201.
Pawelek, J. M., Chakraborty, A. K. (1998). The enzymology of melanogenesis. In The Pigmentary System:
Physiology and Pathophysiology(Nordlund, J. J., Boissy, R. E., Hearing, V. J., King, R. A., Ortonne, J.
P., ed.eds), pp. 391-400. Oxford University Press, New York.
Pawelek, JM and Korner, A. M. (1982). The biosynthesis of mammalian melanin. Amer. Sci. 70: 136-145.
Paya M, Ferrandiz F, Miralles C, et al. (1993). Effects of counarin derivatives on superoxide anion
generation. Arzneimittel Forsch. 43: 655.
Polte, T. and Tyrrell, R. M. (2004). Involvement of lipid peroxidation and organic peroxides in UVA-induced
matrix metalloproteinase-1 expression. Free Radical Biology & Medicine. 36: 1566-1574.
Potterf, S. B., V. Virador, K. Wakamatsu, M. Furumura, C. Santis, S. Ito and V. J. Hearing. (1999). Cysteine
transport in melanosomes from murine melanocytes. Pigment Cell Res. 12: 4-12.
Prota, G. (1992). An introduction to melanin research. In: Melanins and
Melanogenesis. New York: Academic Press, p.277-290.
Rees, J. L. (2000). The melanocortin 1 receptor (MC1-R): more than just red hair. Pigment Cell Res. 13: 135-
140.
Robert, L. and Keys, K. (1997). The spectral dependence for UVA-induced cumulative damage in human skin. J.
Invest. Dermatol. 108: 17-21.
Rutao Cui, Hans R. Widlund, Erez Feige, Jennifer Y. Lin, Dara L. Wilensky, Viven E. Igras, John D’Orazio,
Claire Y. Fung, Carl F. Schanbacher, Scott R Granter, and David E. Fisher. (2007). Central
Role of p53 in the Suntan Response and Pathologic Hyperpigment-ation. Cell. March 9. 128:853-864.
Sánchez-Ferrer ,A., Rodríguez-López, J. N., García-Cánovas, F and García-Carmona, F.(1995). Tryrosinase: a
comprehensive review of is mechanism. Biochim. Biophys.Acta. 1247: 1-11.
Scharffetter-Kochanek, K., M. Wlaschek, P. Brenneisen, M. Schauen, R. Blaudschun and J. Wenk. (1997). UV-
induced reactive oxygen species in photocarcinogenesis and photoaging. Biol. Chem. 378: 1247-1257.
Schwarz, A., Bhardwaj, R., Aragane, K., Mahnke, C., Riemann, J., Metze, D., Luger, T.A., and Schwarz, T.
(1995). Ultraviolet-B-inducedapoptosis of keratinocytes: evidence for partial involvement of tumor
necrosis factor-alpha in the formation of sunburn cells. J. Invest. Dermatol. 104: 922-927.
Setaluri, V. (2003). The melanosome: dark pigment granule shines bright light on vesicle biogenesis and
more. J. Invest. Dermatol. 121: 650-60.
Shampa M., Simon K. S., Chinmoy S., Bidisha S., Ranjan B., (2005). Human placental lipid induces
melanogenesis byincreasing the expression of tyrosinase and its related proteins in vitro. Pigment Cell
Res. 18: 25-33.
Shibuya T.,Murota T.,Salamoto K.,Iwahara S.,Ikeno M., (1982). “Mutagenicity and dominant lethal test of
kojic acid-Ames test, forward mutation test on cultured Chinese hamsters cell and dominant lethal test in
mice”, J. Toxicol. Sci.,7: p.255-262.
Shindo Y., Hashimoto T., (1998). Ultraviolet B-induced cell death in four cutaneous cell ines exhibiting
different enzymatic antioxidant defences: involvement of apoptosis. J. Dermatol. Sci. 17(2): 140-150.
Siegrist, W. and A. N. Eberle. (1995). Melanocortins and their implication in melanoma. Trends Endocrinol.
Metab. 6:114-120.
Skov, LH. Hansen, J. N. W. N. Barker, J. Simon and O. Baadsgaard. (1997). Contrasting effects of ultraviolet-
A and ultraviolet-B exposure on induction of contact sensitivity in human skin. Clin. Exp. Immunol.107:
585-588.
Slominski, A. and J. Pawelek. (1998). Animals under the sun: effects of ultraviolet radiation on mammalian
kin. Clin. Dermatol. 16: 503-515.
Smith, R., E. Healy, S.Siddiqi, N. Flanagan, P. M. Steinlen, I. Rosdahl, J. P. Jacques, S. Rogers, R.
Turner, I. J. Jackson, M. A. Birch-Machin and J. L. Ree. (1998). Melanocortin 1 receptor variants in an
Irish population. J. Invest. Dermatol. 111: 119-122.
Stefania Briganti, Emanuela Camera and Mauro Picardo, (2003). "Chemical and Instrumental Approaches to Treat
Hyperpigmentation", Pigment Cell Research, Vol. 16: 101-110.
Stuart Ira Fox 原著，甘淑芬等譯 (2007)。人體生理學，高立圖書出版發行
Sturm, A. (1998). Human pigmentation genes and their response to solar UV radiation. Mutat. Res. 422: 69-76.
Sturm, R. A., OSullivan, B. J., Box, N. F., Smith, A. G., Smit,S. E., Puttick, E. R., Parsons, P. G. and
Dunn, I. S. (1995).Chromosomal structure of the human TYRP1 and TYRP2 Cell. Mol. Life Sci. Vol.
66, (2009). loci and comparison of the tyrosinase-related protein gene family. Genomics 29: 24-34.
Sulaimon SS, Kitchell BE. (2003) . The biology of melanocytes. Vet Dermatol; 14(2):57-65.
Sulaimon, S. S. and B. E. Kitchell. (2003). The biology of melanocyte. Vet. Dermartol. 14: 57-65.
Takahashi Y, Ishikawa O, Okada K, Ohnishi K, Miyachi Y. (1995). Disaccharide analysis of the skin
glycosaminoglycans in chronically ultraviolet light-irradiated hairless mice. J Dermatol Sci. Sep;10
(2):139-44.
Takakazu, S. and Stan, P. (1993). Differences in subcellular distribution of catechol-O-methyltransferase
and tyrosinase in malignant melanoma. Journal of Investigative Dermatology. 100: 222S-225S.
Tanaka T, Kawamori T, Ohnishi M, Okamoto K, Mori H, Hara A. (1994). Chemoprevention of 4-nitroquinoline 1-
oxide-induced oral carcinogenesis by dietary protocatechuic acid during initiation and postinitiation
phases. Cancer Res. 1;54(9):2359-65.
Tanaka T, Kojima T, Kawamori T, and Mori H. (1995).Chemoprevention of digestive organs carcinogenesis by
natural product protocatechuic acid. Cancer supplement; 75: 1433-1439.
Tanaka T, Kojima T, Kawamori T, et al. (1993). Chemoprevention of diethylnitrosamine-induced
hepatocarcinogenesis by a simple phenolic acid, protocatechuic acid in rats. Cancer Res; 53:2775-2779.
Tanaka T, Kojima T, Suzuki M, Mori H. (1993). Chemoprevention of colon carcinogenesis by the natural product
of a sample phenolic compound protocatechuic acid: suppressing effects on tumor development and biomarker
expression of colon tumorigenesis. Cancer Res; 53: 3908-3913.
Tanaka, T. Kawamori, T. Ohnishi, K. Okamoto, T. Mori, K. Hara, (1994). Chemoprevention of 4-nitroquinoline-1-
oxide induced oral carcinogenesis by dietary protocatechuic acid during initiation and post-initiation
phase. Cancer Res, 54:2359-2365.
Toews, G. B., P. R. Bergstresser and J. W. Streilein. (1980). Epidermal Langerhans cell density determines
whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB. J. Immunol. 124:
445-453.
Tomaino A., Cristani M., Cimino F., Special A., Trombetta D., Bonina F., Saija A., (2006). In vitro
protective effect of a Jacquez grapes wine extract on UVB-induced skin damage. Toxicol. In Vitro. 20:
1395-1402.
Tortora G. J., Anagnostakis N. P., Principles of Anatomy and Physiology, Happer & Row Publisers. (1990). New
York.Tang, A. and M. C. Udey. (1991). Inhibition of epidermal Langerhans cell function by low dose
ultraviolet B radiation. Ultraviolet B radiation selectively modulates ICAM-1 (CD54) expression by murine
Langerhans cells. J. Immunol. 146: 3347-3355
Tour W. (1990). Increasing the effectiveness, Cosm. Toil. 105: 79-85.
Tsatmali, M., Ancans, J., Yukitake, J., and Thody, A.J. (2000). Skin POMC peptides: their actions at the
human MC-1 receptor and roles in the tanning response. Pigment Cell Res. 13 (Suppl 8) : 125-129.
Tseng TH, Wang CJ, Kao ES, and Chu HY. (1996). Hibiscus protocatechuic acid protects against oxidative
damage induced by tert-butylhydroperoxide in rat primary hepatocytes. Chemico-Biological Interaction,
101:137-148.
Ulrich, S. E. (1995). The role of epidermal cytokines in the generation of cutaneous immune reactions and
ultraviolet radiation-induced immune suppression. Photochem. Photobiol. 62: 389-404.
Ulrich, S. E. (2002). Photo immune suppression and photocarcinogenesis. Front. Biosci. 7: 684-703.
Urbach, F. (1997). Ultraviolet radiation and skin cancers in humans. J. Photochem. Photobiol. B 40: 3-7.
Valverde, P, E. Healy, R. Jackson, J. Rees and A. J. Thody. (1995). Variants of the melanocyte-stimulating
hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet. 11: 328-330.
Varani, J., D. Spearman, P. Per One, S. E. G. Flagyl, S.Datta and Z. Q.(2001). Inhibition of type І
procollagen synthesis by damaged collagen in photoaged skin and by collagenase-degraded collagen in
vitro. Am. J. Pathol. 158: 931-942.
Weiss, J. M., A. C. Renkl, R. W. Denfeld, R. de Roche, B. Spitzlei, E. Schöpf and J. C. Simon. (1995). Low-
dose UVB radiation perturbs the functional expression of B7.1 and B7.2 co-stimulatory molecules on human
Langerhans cells. Eur. J. Immunol. 25: 2858-2862.
Wickett RR, Visscher M. (2006). Structure and function of the epidermal barrier. Am J Infect Control. 34:
S98-110.
Wintzen, M. and B. A.Gilchrest. (1996). Propiomelanocortin, its derived peptides, and skin. J. Invest.
Dermatol. 106: 3-10.
Winzen, M., Yaar, M., Burbach, J.P.H., and Gilchrest, B.A. (1996). Proopio-melanocortin gene product
regulation in keratinocytes. J. Invest. Dermatol. 106: 673-678.
Wu, JH. and Park, H. Y. (2003). Protein kinase C-beta-mediated complex formation between tyrosinase and TRP-
1. Biochem. Biophys. Res. Commun. 311: 948-953.
Yaar, M. and B. A. Gilchrest. (2001). Skin aging: postulated mechanisms and consequent changes in structure
and function. Clin. Geriatr. Med. 17: 617-630.
Yang, S., G. J. Fisher and J. J. Voorhees. (2001). Photoaging: pathogenesis, prevention and treatment. Clin.
Geriatr. Med. 17: 643-659.
Yen-Hua Huang, Tzong-Huei Lee, Kuei-Jung Chan, Feng-Lin Hsu, Yu-Chih Wu, Mei-Hsien Lee* (2008). Anemonin is
a natural bioactive compound that can regulate tyrosinase-related proteins and mRNA in human melanocytes.
Journal of Dermatological Science;49: 115-123.
Yoshiki, M. (1995). Photoaging from an oxidative standpoint. J. Dermatol. Sci. 9: 79-86.
Yoshinori, T., Michihiro, H. and Katsunori, A. (1996).The relationship between quantitative change in
collagen and formation of wrinkles on hairless mouse skin after chronic UV irradiation. J. Dermatol. Sci.
12: 56-63.
Young, Barbara (2002)。功能性組織學，合記圖書出版社。
Yumiko, T., Osamu, I., Katsuyuki, O., Kazunori, A. and Yoshiki, M. (1996). Disaccharide analysis of human
skin glycosaminoglycans in sun-exposed and sun-protected skin of aged people. J. Dermatol. Sci.11:
129-133.
Yumiko, T., Osamu, I., Katsuyuki, O., Kazunori, O. and Yoshiki, M. (1995). Disaccharide analysis of the skin
glycosaminoglycans in chronically ultraviolet light-irradiated hairless mice. J. Dermatol. Sci. 10:
139-144.