α-synuclein蛋白及抑制剂对酪氨酸酶的调控机制
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摘要
酪氨酸酶(EC．1．14．18．1)是一种广泛存在于自然界中含铜的金属氧化酶，它具有单酚酶活性，可以将酪氨酸羟化形成L-多巴(L-DOPA)，也具有二酚酶活力，将L-多巴氧化成多巴醌。它是生物形成黑色素合成的关键酶，决定了皮肤和头发色素的颜色。酪氨酸酶的异常表达引起了各种各样的皮肤病，如老年斑及光照损伤等。它还与人脑中的神经黑色素形成及神经退行性病变相关的帕金森病有关，因此酪氨酸酶抑制剂临床应用于与黑色素失调相关疾病的治疗。其在美白化妆品及日晒变黑应用方面具有重要作用。
本论文从天然植物中分离纯化出对酪氨酸酶具有很强抑制作用的抑制剂并探讨其对单酚酶和二酚酶活性的抑制作用机理。再以小鼠B16F10细胞的酪氨酸酶为研究对象，研究其对黑色素生成量的影响及其相关基因的转录调控机制。最后，以果蝇为动物模型研究酪氨酸酶抑制剂对酪氨酸酶代谢途径中相关产物多巴胺生成量的影响。在筛选酪氨酸酶抑制剂过程中，发现了与帕金森病相关的α-synuclein蛋白的过表达能显著抑制黑色素的生成量，这预示着酪氨酸酶与帕金森病可能有着某种相关性，因此研究了α-synuclein蛋白对小鼠B16F10细胞酪氨酸酶转录调控的机制。相关研究内容和结果如下：
(1)对酪氨酸酶有抑制作用的化合物：Cardol trienes，Cardol diene，Cardnol trienes，Cardanol diene，Cardanol monone，研究了它们对对酪氨酸酶的抑制机理及对小鼠B16F10细胞的黑色素生成量的影响及其相关基因的转录调控机制。
(2)从抗生素药品中筛选了对酪氨酸酶有制作用的药物，研究其对酪氨酸酶的抑制机理。
(3)以果蝇为动物模型研究酪氨酸酶抑制剂对酪氨酸酶代谢途径中相关物质含量的影响。
(4)研究了α-synuclein蛋白过表达对小鼠B16F10细胞的酪氨酸酶转录调控的机制。
Tyrosinase (1.14.18.1),widely distributed in nature,is a metalloenzyme oxidasewhich catalyzes two distinct reactions of melanin synthesis---the hydroxylation ofmonophenol and the oxidation of o-diphenol to the corresponding o-quinone.It is akey enzyme in melanin biosynthesis,involved in determining the color of mammalianskin and hair.Its abnormal expression is responsible for the various dermatologicaldisorders,such as melasama age spots,actinic damages.It also contributes toneuromelanin formation in the human brain and the neurodegeneration associatedwith Parkinson's disease.Tyrosinase inhibitors,therefore,should be clinically usefulfor the treatments of some dermatological disorders associated with melaninhyperpigmentation and also important in cosmetics for whitening and depigmentationafter sunburn.The inhibition of tyrosinase has been the subject of many studies.
In the present paper,we Separate inibitors from natural plants and effects of themon the activity of mushroom tyrosniase have been studied.Then effects of them on themelanin content and regulation of melanogenesis have been studied.In the end,effects of inhibitors on dopamine content in fly were assay.In the process of ourscreening the tyrosinase inhibitors,we found that melanin content could be depressionby overexpressingα-synuclein in the cell.The result indicates that tyrosinase andParkinson's disease have correlation to some extent,so the regulation of tyrosinase inthe B 16F10 has been studied.The contents and results were as follows:
Five compounds were seperated that can inhibit tyrosinase from CNSL:Cardoltrienes,Cardol diene,Cardnol trienes,Cardanol diene,Cardanol monone.Theinhibition mechanism of them against the activity of mushroom tyrosinase wasstudied.Effects of them on the melanin content and regulation of melanogenesis inthe B 16F 10 cell were also studied.
Screening the tyrosinase inhibitors from drugs and studying their inhibitorymechanism have been conducted.
Effects of inhibitors on dopamine content in fly were assay.Regulation ofmelanogenesis by overexpressingα-synuclein in the B 16F 10 was also studied.
本论文从天然植物中分离纯化出对酪氨酸酶具有很强抑制作用的抑制剂并探讨其对单酚酶和二酚酶活性的抑制作用机理。再以小鼠B16F10细胞的酪氨酸酶为研究对象，研究其对黑色素生成量的影响及其相关基因的转录调控机制。最后，以果蝇为动物模型研究酪氨酸酶抑制剂对酪氨酸酶代谢途径中相关产物多巴胺生成量的影响。在筛选酪氨酸酶抑制剂过程中，发现了与帕金森病相关的α-synuclein蛋白的过表达能显著抑制黑色素的生成量，这预示着酪氨酸酶与帕金森病可能有着某种相关性，因此研究了α-synuclein蛋白对小鼠B16F10细胞酪氨酸酶转录调控的机制。相关研究内容和结果如下：
(1)对酪氨酸酶有抑制作用的化合物：Cardol trienes，Cardol diene，Cardnol trienes，Cardanol diene，Cardanol monone，研究了它们对对酪氨酸酶的抑制机理及对小鼠B16F10细胞的黑色素生成量的影响及其相关基因的转录调控机制。
(2)从抗生素药品中筛选了对酪氨酸酶有制作用的药物，研究其对酪氨酸酶的抑制机理。
(3)以果蝇为动物模型研究酪氨酸酶抑制剂对酪氨酸酶代谢途径中相关物质含量的影响。
(4)研究了α-synuclein蛋白过表达对小鼠B16F10细胞的酪氨酸酶转录调控的机制。
Tyrosinase (1.14.18.1),widely distributed in nature,is a metalloenzyme oxidasewhich catalyzes two distinct reactions of melanin synthesis---the hydroxylation ofmonophenol and the oxidation of o-diphenol to the corresponding o-quinone.It is akey enzyme in melanin biosynthesis,involved in determining the color of mammalianskin and hair.Its abnormal expression is responsible for the various dermatologicaldisorders,such as melasama age spots,actinic damages.It also contributes toneuromelanin formation in the human brain and the neurodegeneration associatedwith Parkinson's disease.Tyrosinase inhibitors,therefore,should be clinically usefulfor the treatments of some dermatological disorders associated with melaninhyperpigmentation and also important in cosmetics for whitening and depigmentationafter sunburn.The inhibition of tyrosinase has been the subject of many studies.
In the present paper,we Separate inibitors from natural plants and effects of themon the activity of mushroom tyrosniase have been studied.Then effects of them on themelanin content and regulation of melanogenesis have been studied.In the end,effects of inhibitors on dopamine content in fly were assay.In the process of ourscreening the tyrosinase inhibitors,we found that melanin content could be depressionby overexpressingα-synuclein in the cell.The result indicates that tyrosinase andParkinson's disease have correlation to some extent,so the regulation of tyrosinase inthe B 16F10 has been studied.The contents and results were as follows:
Five compounds were seperated that can inhibit tyrosinase from CNSL:Cardoltrienes,Cardol diene,Cardnol trienes,Cardanol diene,Cardanol monone.Theinhibition mechanism of them against the activity of mushroom tyrosinase wasstudied.Effects of them on the melanin content and regulation of melanogenesis inthe B 16F 10 cell were also studied.
Screening the tyrosinase inhibitors from drugs and studying their inhibitorymechanism have been conducted.
Effects of inhibitors on dopamine content in fly were assay.Regulation ofmelanogenesis by overexpressingα-synuclein in the B 16F 10 was also studied.
引文
[1] Robb DA. In: Lontie R, editor. Copper proteins and copper enzymes. Boca Raton, FL: CRC Press; 1984. p 207-241.
[2] Xu Y, Stokes AH, Freeman WM, et al. Tyrosinase mRNA is expressed in human substantia nigra. Mol Brain Res 1997, 45: 159-162.
[3] Palumbo A, D'Ischia M, Misuraco G, et al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta 1991, 1073:85-90.
[4] Maeda K, Fukuda M. In vitro effectiveness of several whitening cosmetic components in human melanocytes. J. Soc Cosmet Chem 1991, 42: 361-368.
[5] Ohyama Y, mishima. Y. Melanogenesis-inhibitory effect of kojic acid and its action mechanism. Fragrance J, 1990, 6:53-57.
[6] Robit C, Rouch C, Cadet F. Inhibition of palmito(Acanthophoenix rubra) polyphenol oxidase by carboxylic acids. Food Chem 1997, 59: 355-360.
[7] Espin JC,Wichers HJ. Slow-binding inhibition of mushroom (Agaricus bisporus) tyrosinase isoforms by tropolone. J. Agric Food Chem. 1999, 47: 2638-2644.
[8] Xie LP, Chen QX, Huang H, et al. Inhibitory Effects of Some Flavonoids on the Activity of Mushroom Tyrosinase. Biochem (Moscow) 2003; 68: 487-491.
[9] Kahn V, Ben-ShalomN, Zakin V. Effect of kojic acid on the oxidation of N-acetyldopamine by mushroom tyrosinase. J Agric Food Chem, 1997; 45: 4460-4465.
[10] Song KK, Chen QX, Wang Q, et al. Inhibitory effects of 4-vinylbenzaldehyde and 4-vinylbenzoic acid on the activity of mushroom tyrosinase. J Enz Inhib Med Chem 2005,20(3):239-243.
[11] Espin JC, Wichers HJ. Effect of captopril on mushroom tyrosinase activity in vitro. Biochim Biophys Acta 2001, 1544: 289-300.
[12] Andrawis A, Khan V. Effect of methimazole on the activity of mushroom tyrosinase. Biochem J, 1986, 235: 91-96.
[13] Solomon, EI, Sundaram, UM, Machonkin, TE. Multicopper Oxidases and oxygenases. Chem. Rev. 1996, 96:2563-2606
[14] Himmelwright R S, Eickman N C, LuBien C D, et al. Chemical and spectroscopic studies of the binuclear copper active site of Neurospora tyrosinase: comparision to hemocyanins[J]. J. Am. Chem. Soc, 1980, 102: 7339-7344.
[15] Gerdemann C, Eicken C, Krebs B. The crystal structure of catechol oxidase: new insight into the function of type-3 copper proteins[J]. Acc. Chem. Res, 2002, 35: 183-191.
[16] Volbeda A, Feiters MC, Vincent MG., et al. Spectroscopic investigations of Panulirus interruptus hemocyanin in the crystalline state. Eur. J. Biochem. 1989, 181: 669-673
[17] Volbeda A, Hol WG. Crystal structure of hexameric haemocyanin from Panulirus interruptus refined at 3.2 A resolution.. J. Mol. Biol. 1989, 209: 249-279
[18] Hazes B, Magnus KA, Bonaventura C, et al. Crystal structure of deoxygenated Limulus polyphemus subunit Ⅱ hemocyanin at 2.18 A resolution: clues for a mechanism for allosteric regulation. Protein Sci. 1993, 2:597-619.
[19] Hazes B, Magnus KA, Kalk, KH, et al. Nitrate binding to Limulus polyphemus subunit type Ⅱ hemocyanin and its functional implications.J. Mol. Biol. 1996, 262, 532-541.
[20] Magnus KA, Hazes B, Ton-That H, et al. Crystallographic analysis of oxygenated and deoxygenated states of arthropod hemocyanin shows unusual differences. Proteins. 1994, 19:302-309.
[21] Cuff ME, Miller KI, van Holde KE, et al. Crystal structure of a functional unit from Octopus hemocyanin. J.Mol. Biol. 1998, 278: 855-870.
[22] Klabunde T, Eicken C, Sacchettini JC, et al. Crystal structure of a plant catechol oxidase containing a dicopper center. Nat. Struct. Biol. 1998,5:1084-1090
[23] Matoba Y, Kumagai T, Yamamoto A, et al. Crystallographic evidence that the dinuclear copper center of tyrosinase is flexible during catalysis[J]. The Journal of Biological Chemistry, 2006, 281(13): 8981-8990.
[24] 李韶勇, 孙命, 曲娜, 等. 黑色素的合成及其常见抑制剂的作用机理[J] .天津师范大学学报, 2002, 22(1): 17-22.
[25] Kong KH, Hong MP. Purification and characterization of a highly stable tyrosinase from Thermomicrobium roseum [J]. Biotechnology and Applied Biochemistry. 2000, 31: 113-118
[26] Nishioka K. Particulate tyrosinase of human melanoma[J]. European Journal of Biochemistry, 1978, 85: 137-146.
[27] Giebel LB, Strunk KM., Spritz RA. Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment[J]. Genomics, 1991, 9: 435-445.
[28] Mochii M, Iio A., Yamamoto H. Isolation and characterization of a chicken tyrosinase cDNA[J]. Pigment. Cell Res., 1992, 5: 162-167.
[29] Kwon BS, Wakulchik M, Haq AK. Sequence analysis of mouse tyrosinase cDNA and the effect of melanotropin on its gene expression[J]. Biochem. Biophys. Res. Commun, 1988, 153:1301-1309.
[30] Ebbelaar C.E.M, Wichers HJ, Van Den Bosch T. Characterization of fruiting body expressed gene encoding a putative tyrosinase in Agaricus bisporus. Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases. [31] Bernan V, Filpula D, Herber W. The nucleotide sequence of the tyrosinase gene from Streptomyces antibioticus and characterization of the gene product[J]. Gene, 1985, 37:101-110.
[32] Yamamoto H, Kudo T, Masuko N. Phylogeny of regulatory regions of vertebrate tyrosinase genes[J]. Pigment Cell Res., 1992, 5: 284-294.
[33] Rosei MA, Mosca L, De Marco C. New possible pathways for melanogenesis: opiomelanins[J]. Recenti Prog Med. 1997, 88 (3): 134-139.
[34] Mason HS. Oxidases. in Annu. Rev. Biochem., 1965, 34: 595-634.
[35] Prota G. Recent advances in the chemistry of melanogenesis in mammals. J. Invest. Dermatol., 1980, 75: 122-127.
[36] 潘兴华, 陈志龙, 黄丽娜, 黑素细胞及黑素的生成与调节. 生理科学进展, 1998, 29 (2): 179-182.
[37] Fenoll LG, Rodriguez-Lopez J N, Garcia-Sevilla F, et al. Analysis and interpretation of the action mechanism of mushroom tyrosinase on monophenols and diphenols generating highly unstableo-quinones[J]. Biochimica et Biophyica Acta, 2001, 1548: 1-22.
[38] Cabanes J, Garcia-Canovas F, Lozano J A, et al. A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]. Biochim. Biophys. Acta, 1987, 923: 187-195.
[39] Beltramini M, Salvato B, Santamaria M, et al. The reaction of CN- with the binuclear copper site of Neurospora tyrosinase： its relevance for a comparison between tyrosinase and hemocyanin active sites[J]．Biochim．Biophys．Acta．， 1990， 1040(3)： 365-372．
[40]Gaykema W PJ， Hol W G J， Vereijken J M， et al．3．2 (?) structure of the copper-containing，oxygen-carrying protein Panulirus interruptus haemocyanin[J]．Nature， 1984， 309(5963)：23-29．
[41]Van Gastel M， Bubacco L， Groenen E J J， et al．EPR study of the dinuclear active copper site of tyrosinase from Streptomyces actibioticus[J]．FEBS Letters， 2000， 474： 228-232．
[42]Alzuet G，Bubacco L， Casella L， et al．The binding of azide to copper-containing and cobalt-containing forms of hemocyanin from the mediterranean crab Carcinus aestuarii[J]．Eur．J．Biochem．， 1997， 247(2)： 688-694．
[43]Cabanes J， Garc(?)a-C(?)novas F， Lozano J A， et al．A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]．Biochim．Biophys．Acta， 1987， 923： 187-195．
[44]Rodr(?)guez-L(?)pez JN， Fenoll L G， Garc(?)a-Ruiz P A， et al．Stopped-flow and steady-state study of the diphenolase activityof mushroom tyrosinase[J]．Biochemistry， 2000， 39：10497-10506．
[45]陈清西，宋康康．酪氨酸酶的研究进展[J]．厦门大学学报(自然科学版)，2006， 45(5)：731-737．
[46]Chen QX， Song K K， Wang Q， Huang H．Inhibitory effects of mushroom tyrosinase by some alkylbenzaldehydes[J]．Journal of Enzyme Inhibition and Medicinal Chemistry， 2003，18(6)： 491-496．
[47]Cabanes J， Garc(?)a-C(?)novas F， Lozano J A， et al．A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]．Biochim．Biophys．Acta， 1987， 923： 187-195．
[48]Rodr(?)guez-L(?)pez J N， Tudela J， Var(?)n R， et al．Analysis of a kinetic model for melanin biosynthesis pathway [J]．J．Biol．Chem．， 1992， 267： 3801-3810．
[49]Fenoll L G， Rodr(?)guez-L(?)pez J N， Garc(?)a-Sevilla F et al．Analysis and interpretation of the action mechanism of mushroom tyrosinase on monophenols and diphenols generating highly unstableo-quinones [J]．Biochimica et BiophyicaActa， 2001，1548： 1-22．
[50]Mary S R， Manuel R．Specific Tyrosinases Associated with Melanoma Replicative Senescence and Melanogenesis[J]．CANCER RESEARCH， 1993， 53(1)： 2469-2471．
[51] Ling H, Heinz A, William JP. Interspecies difference in the regulation of melanocyte development by SOX10 and MITF [J]. PNAS, 2006, 103(24): 9081-9085.
[52] Akiha K, Mayuko K, Akir S, et al. Mitf contributes to melanosome distribution and melanophore dendricity[J]. Pigment Cell Melanoma Res, 2007, 21: 56-62.
[53] Toshihiko H, Jacqueline M, Wilfred D, et al. The Repeat Domain of the Melanosomal Matrix Protein PMEL17/GP100 Is Required for the Formation of Organellar Fibers[J]. J. Biol. Chem, 2006, 281(30): 21198-21208.
[54] Yuji Y, Michaela B, Vincent JH, the Regulation of Skin Pigmentationo[J]. J. Biol Chem, 2007, 282(38): 27557-27561.
[55] Douglas MM, Seema G, and Lee B. Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediatedSubstrate Phosphorylation [J]. J. Biol. Chem, 2005, 280(51): 42051-42060.
[56] Zalfa A. A, Ana L K, Renny J. K. Melanoma prevention strategy based on using tetrapeptide α -MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity [J]. FASEB J, 2006, 20: 888-896.
[57] Gertrude-E. C, Vincent JH. Human skin pigmentation: melanocytes modulate skin color in response to stress [J]. FASEB J, 2007, 21: 976-994.
[58] Roser B, Robert B. Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation [J]. PIGMENT CELL RES, 2000, 13: 60-69.
[59] Kazuo K, Steven JO, Rene G. Microphthalmia Transcription Factor as a Molecular Marker for Circulating Tumor Cell Detection in Blood of Melanoma Patients [J]. Clin Cancer Res 2006, 12(4): 1137-1143.
[60] Chen YM, Walter C. Melanogenesis in Human Melanomas [J]. Cancer Res 1975, 35: 606-612.
[61] Nicolas D, Robert H, Jan M, et al. In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling [J]. Cancer Res 2006, 66 (19): 9483-9491.
[62] Mary SR, Manuel R. Specific Tyrosinases Associated with Melanoma Replicative Senescence and Melanogenesis [J]. Cancer Res, 1993, 53: 2469-2471.
[63] Genji I, Yutaka M. Loss of Melanogenic Properties in Tyrosinases Induced by Glycosylation Inhibitors within Malignant Melanoma Cells [J]. Cancer Res, 1982, 42: 1994-2002.
[64] Kowichi J, Yasuhiro M, Koichi H, et al. Characterization of Melanogenesis and Morphogenesis of Melanosomes by Physicochemical Properties of Melanin and Melanosomes in Malignant Melanoma [J]. Cancer Res, 1984, 44: 1128-1134.
[65] Sungbin I, Osamu M, Fuping P, et al. Activation of the Cyclic AMP Pathway by a-Melanotropin Mediates the Response of Human Melanocytes to Ultraviolet B Radiation [J]. Cancer Res, 1998, 58: 47-54.
[66] Solano F, Briganti S, Picardo M, et al. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects [J]. Pigment Cell Res., 2006, 19: 550-571.
[67] Park H Y, Wu C, Yonemoto L, et al. MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes [J]. Biochem. J., 2006, 395(3): 571-578.
[68] Lee J, Jung E, Park J, et al. Glycyrrhizin induces melanogenesis by elevating a cAMP level in b16 melanoma cells [J]. J. Invest. Dermatol., 2005, 124(2): 405-411.
[69] Yang JY, Koo JH, Song YG, et al. Stimulation of melanogenesis by scoparone in B16 melanoma cells [J]. Acta Pharmacol. Sin., 2006, 27(11): 1467-1473.
[70] Lin CB, Babiarz L, Liebel F, et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation [J]. J. Invest. Dermatol., 2002, 119: 1330-1340.
[71] Kim KS, Kim JA, Eom SY, et al. Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression [J]. Pigment Cell Res., 2006, 19(1): 90-98.
[72] Saito H, Yasumoto K, Takeda K, et al. Microphthalmia-associated transcription factor in the Wnt signaling pathway [J]. Pigment Cell Res., 2003, 16(3): 261-265.
[73] Perez-Bernal A, Munoz-Perez MA, Camacho F. Management of facial hyperpigmentation [J]. American Journal of Clinical Dermatology, 2000, 1(5): 261-268.
[74] Victor FC, Gelber J, Rao B. Melasma: a review [J]. Journal of Cutaneous Medicine and Surgery, 2004, 8(2): 97-102. Perez-Bernal A, Munoz-Perez M A, Camacho F. Management of facial hyperpigmentation [J]. Am. J. Clin. Dermatol., 2000, 1(5): 261-268.
[75]Briganti S， Camera E， Picardo M．Chemical and instrumental approaches to treat hyperpigmentation [J]．Pigment Cell Res．， 2003， 16(2)： 101-110．
[76]Sayre LM， Smith MA， Perry G．Chemistry and biochemistry of oxidative stress in neurodegenerative disease[J]．Curr．Chem．， 2001， 8： 721-738．
[77]Kikuchi A， Takeda A， Onodera H， et al．Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy[J]．Neurobiol．Dis．， 2002， 9： 244-248．
[78]Jenner P．Oxidative stress in Parkinson's disease[J]．Ann．Neurol， 2003， 53： S26-S36．
[79]Ben-Shachar D， Zuk R， Glmka Y．Dopamine neurotoxicity： inhibition of mitochondrial respiration[J]．J．Neurochem．1995， 64： 718-723．
[80]Smythies J， Galzigna L．The oxidative metabolism of catecholamines in the brain： a review[J]．Biochim．Biophys．Acta．， 1998， 1380： 159-162．
[81]Xu Y， Stokes AH， Roskoski R， et al．Dopamine， in the presence of tyrosinase， covalently modifies and inactivates tyrosine hydroxylase[J]．J．Neurosci．Res．， 1998， 54： 691-697．
[82]Stokes A H， Hastings T G， Vrana KE．Cytotoxic and genotoxic potential of dopamine[J]．J．Neurosci．Res．1999， 55： 659-665．
[83]Cavalieri EL， Li KM， Balu N， et al．Catechol ortho-quinones： the electrophilic compounds thatformdepurinatingDNAadductsandcouldinitiatecancerandother diseases[J]．Carcinogenesis， 2002， 23： 1071-1077．
[84]Bolton．2000 Bolton J L， Trush M A， et al．Role of quinones in toxicology[J]．Chem．Res．Toxicol．， 2000， 13： 135-160．
[85]Polymeropoulos MH， Lavedan C， Leroy E， et al．Mutation in the alpha-synuclein gene identified in families with Parkinson's disease[J]．Science， 1997， 276： 2045-2047．
[86]Conway KA， Rochet JC， Bieganski RM， et al．Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct[J]．Science， 2001，294： 1346-1349．
[87]李小迪．色素沉着与美白护肤品[J]．香料香精化妆品， 2002， 1：29-31．
[88]刘宇红，董银卯，李才广．皮肤化学美白剂抑制酪氨酸酶活性的研究[J]．日用化学工业，2001，31(1)：21-23．
[89]芮斌，蒋惠亮，淘文沂．美白添加剂—曲酸衍生物[J]．精细与专用化学品，2002， 9：13-14．
[90] 蒋人俊, 汤智 凌, 殷雷等. 美白化妆品的研制[J] 。中外轻工科技, 1998,3:3-5.
[91] Laveda F, Nunez-Delicado E, Garcia-Carmona F, et al. Proteolytic activation of latent Paraguaya peach PPO. Characterization of monophenolase activity [J]. J. Agric. Food Chem., 2001, 49(2): 1003-1008.
[92] Chisari M, Barbagallo RN, Spagna G. Characterization of polyphenol oxidase and peroxidase and influence on browning of cold stored strawberry fruit [J]. J. Agric. Food Chem., 2007, 55(9): 3469-3476.
[93] Spagna G, Barbagallo RN, Chisari M, et al. Characterization of a tomato polyphenol oxidase and its role in browning and lycopene content [J]. J. Agric. Food Chem., 2005, 53(6): 2032-2038.
[94] Busch JM. Enzymic browning in potatoes: a simple assay for a polyphenol oxidase catalysed reaction [J]. Biochemical Education, 1999, 27: 171-173.
[95] Jiang YM, Duan XW, Joyce D, et al. Advances in understanding of enzymatic browning in harvested litchi fruit [J]. Food Chemistry, 2004, 88: 443-446.
[96] Soliva R C, Elez P, Sebastian M, et al. Evaluation of browning effect on avocado puree preserved by combined methods [J]. Innovative Food Science & Emerging Technologies, 2001, 1:261-268.
[97] Murata M, Nishimura M, Murai N, et al. A transgenic apple callus showing reduced polyphenol oxidase activity and lower browning potential [J]. Biosci. Biotechnol. Biochem., 2001, 65(2): 383-388.
[98] Kessler J C, Rochet J C , Lansbury P T. The N-terminal repeatdomain of alpha-synuclein inhbits beta-sheet and amyloid fibrilformation [J]. Biochemistry, 2003, 42 (3): 672-678.
[99] Maroteaux L, Campanelli, J T, SchellerRH. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal[J]. J.Neurosci., 1988, 8: 2804-2815.
[100] Maroteaux, L and Scheller, R H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane[J]. Mol. Brain Res. 1991(11): 335-343.
[101] Tobe T, Nakajo S, Tanaka A, et al. Cloning and characterization of the cDNA encoding a novel specific 14-kDa protein[J]. J. Neurochem. 1992(59): 1624-1629.
[102] U(?)da, K, Fukushima, H, Masliah, E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease[J]. Proc. Natl. Acad. Sci., 1993, 90(11): 282-286.
[103] Bayer, TA, Jakala, P, Hartmann, T, et al. a-Synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease P-amyloid cores[J]. Neurosci. Lett. 1999, 266: 213-216.
[104] Culvenor, JG, McLean, CA, Cutt, S, et al. Non-Ap component of Alzheimer's disease amyloid (NAC)revisited. NAC and a-synuclein are not associated with Aβ amyloid[J]. Am. J.Pathol. 1999(155): 1173-1881.
[105] Jakes, R, Spillantini, MG, Goedert, M. Identification of two distinct synucleins from human brain[J]. FEBS Lett. 1994(345): 27-32.
[106] George, J M, Jin, H, Woods, et al. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch[J]. Neuron, 1995, 15: 361-372.
[107] M. M. Mouradian, edited. Methods in Molecular Medicine, Parkinson's Disease: Methods and Protocols, Humana Press Inc, Totowa, NJ, vol. 62: 36.
[108] Weinreb, PH, Zhen, W, Poon, AW, et al. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded[J]. Biochemistry, 996(35): 13709-13715.
[109] Moore, DJ,West AB, DawsonVL, et al. Molecular pathophysiology of Parkinson's disease Rev[J]. Neurosci. 2005(28): 57-87.
[110] Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies[J]. Nature 1997,388:839-840.
[111] Lewy, F. H. Paralysis agitans. I. Pathologische Anatomie, in Handbuch der Neurologie, 1912(3) (Lewandowsky, M. and Abelsdorff, G., eds.), Springer,Berlin, pp. 920-933.
[112] Tretiakoff, M. C. (1919) Thesis, University of Paris. [113] Golbe LI, Di Iorio G, BonavitaV,et al. A large kindred with autosomal dominant Parkinson's disease[J]. Ann.Neurol. 1990, 27: 276-282.
[114] Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinson's disease to chromosome 4q21-q23[J]. Science, 1996,274: 1197-1199.
[115] Athanassiadou A, VoutsinasG, Psiouri L, et al. Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding a-synuclein[J]. Am. J. Hum. Genet. 1999,65:555-558.
[116] Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the a-synuclein gene identified in families with Parkinson's disease[J]. Science 1997, 276: 2045-2047.
[117] Gao HM,Paul TK,Kunihiro U, et al. Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration[J]. Neurobiology of Disease, 2008, 28(30): 7687-7698.
[118] Magali P,Tudor F,Liisa M, et al. Aggregated α-SynucleinMediates Dopaminergic Neurotoxicity In Vivo[J]. Neurobiology of Disease, 2007, 27(12): 3338-3346.
[119] Brian MD, Lisa RW, Sheng TH, et al. Calpain-Cleavage of α-Synuclein Connecting roteolytic Processing to Disease-Linked Aggregation[J]. Neurobiology, 2007, 170(5): 1725-1738.
[120] Eliezer M, Edward R, Anthony A, et al. Effects of a-Synuclein Immunization in a Mouse Model of Parkinson's Disease[J]. Neuron, 2005, 46: 857-868.
[121] Jochen K, Youngah S, Eliezer M, et al. Hsp70 Reducesa-Synuclein Aggregation and Toxicity[J]. The Journal of Biological Chemistry 2004, 279(24): 25497-25502.
[122] Abeliovich A, Schmitz Y, Farin I, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system[J]. Neuron, 2000, 25: 239-252.
[123] Chen L, Feany MB. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease[J]. Nat Neurosci, 2005, 8: 657-663.
[124] Chu Y, Kordower JH. Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson's disease? [J]. Neurobiol Dis, 2007, 25: 134-149.
[125] Singleton AB, FarrerM, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease[J]. Science, 2003, 302: 841.
[126] Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies[J]. Nature, 1997,388:839-840.
[127] Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders[J]. Science, 2000,287: 1265-1269.
[128] Richter-Landsberg C, Gorath M, Trojanowski JQ, et al. alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes[J]. J Neurosci Res, 2006, 2: 9-14.
[129] Smith WW, Margolis RL, Li X, et al. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells[J]. J Neurosci., 2005, 25: 5544-5552.
[130] Tofaris GK, Garcia RP, Humby T, et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders[J]. J Neurosci., 2006, 26: 3942-3950.
[131] Uryu K, Richter-Landsberg C, Welch W, et al. Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies[J]. Am J Pathol, 2006, 168:947-9131.
[132] Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease[J]. FASEB J. 2005, 19: 533-542
[133] Takafumi H, Michiko MK, Atsushi T, et al. a-Synuclein facilitates the toxicity of oxidized catechol metabolites: Implications for selective neurodegeneration in Parkinson's disease[J]. FEBS Letters, 2006, 580: 2147-2152.
[134] Hasegawa T, Matsuzaki-Kobayashi M, Takeda A, et al. Alpha-synuclein facilitates the toxicity of oxidized catechol metabolites: implications for selective neurodegeneration in Parkinson's disease[J]. FEBS Lett. 2006, 580: 2147-2152.
[135] Isabella T, Marco B, Francesco V, et al. The Reaction of α -Synuclein with Tyrosinase possible implications for parkinson disease[J]. The Journal of Biological Chemistry, 2008, 283(24): 16808-16817.
[136] P. P. Kumar, R. Paramashivappa, P. J. Vithayathil, et al. Process for Isolation of Cardanol from Technical Cashew (Anacardium occidentale L.) Nut Shell Liquid. J. Agric. Food. Chem. 2002, 50: 4705-4708.
[2] Xu Y, Stokes AH, Freeman WM, et al. Tyrosinase mRNA is expressed in human substantia nigra. Mol Brain Res 1997, 45: 159-162.
[3] Palumbo A, D'Ischia M, Misuraco G, et al. Mechanism of inhibition of melanogenesis by hydroquinone. Biochim Biophys Acta 1991, 1073:85-90.
[4] Maeda K, Fukuda M. In vitro effectiveness of several whitening cosmetic components in human melanocytes. J. Soc Cosmet Chem 1991, 42: 361-368.
[5] Ohyama Y, mishima. Y. Melanogenesis-inhibitory effect of kojic acid and its action mechanism. Fragrance J, 1990, 6:53-57.
[6] Robit C, Rouch C, Cadet F. Inhibition of palmito(Acanthophoenix rubra) polyphenol oxidase by carboxylic acids. Food Chem 1997, 59: 355-360.
[7] Espin JC,Wichers HJ. Slow-binding inhibition of mushroom (Agaricus bisporus) tyrosinase isoforms by tropolone. J. Agric Food Chem. 1999, 47: 2638-2644.
[8] Xie LP, Chen QX, Huang H, et al. Inhibitory Effects of Some Flavonoids on the Activity of Mushroom Tyrosinase. Biochem (Moscow) 2003; 68: 487-491.
[9] Kahn V, Ben-ShalomN, Zakin V. Effect of kojic acid on the oxidation of N-acetyldopamine by mushroom tyrosinase. J Agric Food Chem, 1997; 45: 4460-4465.
[10] Song KK, Chen QX, Wang Q, et al. Inhibitory effects of 4-vinylbenzaldehyde and 4-vinylbenzoic acid on the activity of mushroom tyrosinase. J Enz Inhib Med Chem 2005,20(3):239-243.
[11] Espin JC, Wichers HJ. Effect of captopril on mushroom tyrosinase activity in vitro. Biochim Biophys Acta 2001, 1544: 289-300.
[12] Andrawis A, Khan V. Effect of methimazole on the activity of mushroom tyrosinase. Biochem J, 1986, 235: 91-96.
[13] Solomon, EI, Sundaram, UM, Machonkin, TE. Multicopper Oxidases and oxygenases. Chem. Rev. 1996, 96:2563-2606
[14] Himmelwright R S, Eickman N C, LuBien C D, et al. Chemical and spectroscopic studies of the binuclear copper active site of Neurospora tyrosinase: comparision to hemocyanins[J]. J. Am. Chem. Soc, 1980, 102: 7339-7344.
[15] Gerdemann C, Eicken C, Krebs B. The crystal structure of catechol oxidase: new insight into the function of type-3 copper proteins[J]. Acc. Chem. Res, 2002, 35: 183-191.
[16] Volbeda A, Feiters MC, Vincent MG., et al. Spectroscopic investigations of Panulirus interruptus hemocyanin in the crystalline state. Eur. J. Biochem. 1989, 181: 669-673
[17] Volbeda A, Hol WG. Crystal structure of hexameric haemocyanin from Panulirus interruptus refined at 3.2 A resolution.. J. Mol. Biol. 1989, 209: 249-279
[18] Hazes B, Magnus KA, Bonaventura C, et al. Crystal structure of deoxygenated Limulus polyphemus subunit Ⅱ hemocyanin at 2.18 A resolution: clues for a mechanism for allosteric regulation. Protein Sci. 1993, 2:597-619.
[19] Hazes B, Magnus KA, Kalk, KH, et al. Nitrate binding to Limulus polyphemus subunit type Ⅱ hemocyanin and its functional implications.J. Mol. Biol. 1996, 262, 532-541.
[20] Magnus KA, Hazes B, Ton-That H, et al. Crystallographic analysis of oxygenated and deoxygenated states of arthropod hemocyanin shows unusual differences. Proteins. 1994, 19:302-309.
[21] Cuff ME, Miller KI, van Holde KE, et al. Crystal structure of a functional unit from Octopus hemocyanin. J.Mol. Biol. 1998, 278: 855-870.
[22] Klabunde T, Eicken C, Sacchettini JC, et al. Crystal structure of a plant catechol oxidase containing a dicopper center. Nat. Struct. Biol. 1998,5:1084-1090
[23] Matoba Y, Kumagai T, Yamamoto A, et al. Crystallographic evidence that the dinuclear copper center of tyrosinase is flexible during catalysis[J]. The Journal of Biological Chemistry, 2006, 281(13): 8981-8990.
[24] 李韶勇, 孙命, 曲娜, 等. 黑色素的合成及其常见抑制剂的作用机理[J] .天津师范大学学报, 2002, 22(1): 17-22.
[25] Kong KH, Hong MP. Purification and characterization of a highly stable tyrosinase from Thermomicrobium roseum [J]. Biotechnology and Applied Biochemistry. 2000, 31: 113-118
[26] Nishioka K. Particulate tyrosinase of human melanoma[J]. European Journal of Biochemistry, 1978, 85: 137-146.
[27] Giebel LB, Strunk KM., Spritz RA. Organization and nucleotide sequences of the human tyrosinase gene and a truncated tyrosinase-related segment[J]. Genomics, 1991, 9: 435-445.
[28] Mochii M, Iio A., Yamamoto H. Isolation and characterization of a chicken tyrosinase cDNA[J]. Pigment. Cell Res., 1992, 5: 162-167.
[29] Kwon BS, Wakulchik M, Haq AK. Sequence analysis of mouse tyrosinase cDNA and the effect of melanotropin on its gene expression[J]. Biochem. Biophys. Res. Commun, 1988, 153:1301-1309.
[30] Ebbelaar C.E.M, Wichers HJ, Van Den Bosch T. Characterization of fruiting body expressed gene encoding a putative tyrosinase in Agaricus bisporus. Submitted (JAN-1998) to the EMBL/GenBank/DDBJ databases. [31] Bernan V, Filpula D, Herber W. The nucleotide sequence of the tyrosinase gene from Streptomyces antibioticus and characterization of the gene product[J]. Gene, 1985, 37:101-110.
[32] Yamamoto H, Kudo T, Masuko N. Phylogeny of regulatory regions of vertebrate tyrosinase genes[J]. Pigment Cell Res., 1992, 5: 284-294.
[33] Rosei MA, Mosca L, De Marco C. New possible pathways for melanogenesis: opiomelanins[J]. Recenti Prog Med. 1997, 88 (3): 134-139.
[34] Mason HS. Oxidases. in Annu. Rev. Biochem., 1965, 34: 595-634.
[35] Prota G. Recent advances in the chemistry of melanogenesis in mammals. J. Invest. Dermatol., 1980, 75: 122-127.
[36] 潘兴华, 陈志龙, 黄丽娜, 黑素细胞及黑素的生成与调节. 生理科学进展, 1998, 29 (2): 179-182.
[37] Fenoll LG, Rodriguez-Lopez J N, Garcia-Sevilla F, et al. Analysis and interpretation of the action mechanism of mushroom tyrosinase on monophenols and diphenols generating highly unstableo-quinones[J]. Biochimica et Biophyica Acta, 2001, 1548: 1-22.
[38] Cabanes J, Garcia-Canovas F, Lozano J A, et al. A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]. Biochim. Biophys. Acta, 1987, 923: 187-195.
[39] Beltramini M, Salvato B, Santamaria M, et al. The reaction of CN- with the binuclear copper site of Neurospora tyrosinase： its relevance for a comparison between tyrosinase and hemocyanin active sites[J]．Biochim．Biophys．Acta．， 1990， 1040(3)： 365-372．
[40]Gaykema W PJ， Hol W G J， Vereijken J M， et al．3．2 (?) structure of the copper-containing，oxygen-carrying protein Panulirus interruptus haemocyanin[J]．Nature， 1984， 309(5963)：23-29．
[41]Van Gastel M， Bubacco L， Groenen E J J， et al．EPR study of the dinuclear active copper site of tyrosinase from Streptomyces actibioticus[J]．FEBS Letters， 2000， 474： 228-232．
[42]Alzuet G，Bubacco L， Casella L， et al．The binding of azide to copper-containing and cobalt-containing forms of hemocyanin from the mediterranean crab Carcinus aestuarii[J]．Eur．J．Biochem．， 1997， 247(2)： 688-694．
[43]Cabanes J， Garc(?)a-C(?)novas F， Lozano J A， et al．A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]．Biochim．Biophys．Acta， 1987， 923： 187-195．
[44]Rodr(?)guez-L(?)pez JN， Fenoll L G， Garc(?)a-Ruiz P A， et al．Stopped-flow and steady-state study of the diphenolase activityof mushroom tyrosinase[J]．Biochemistry， 2000， 39：10497-10506．
[45]陈清西，宋康康．酪氨酸酶的研究进展[J]．厦门大学学报(自然科学版)，2006， 45(5)：731-737．
[46]Chen QX， Song K K， Wang Q， Huang H．Inhibitory effects of mushroom tyrosinase by some alkylbenzaldehydes[J]．Journal of Enzyme Inhibition and Medicinal Chemistry， 2003，18(6)： 491-496．
[47]Cabanes J， Garc(?)a-C(?)novas F， Lozano J A， et al．A kinetic study of melanization pathway between L-tyrosine and dopachrome [J]．Biochim．Biophys．Acta， 1987， 923： 187-195．
[48]Rodr(?)guez-L(?)pez J N， Tudela J， Var(?)n R， et al．Analysis of a kinetic model for melanin biosynthesis pathway [J]．J．Biol．Chem．， 1992， 267： 3801-3810．
[49]Fenoll L G， Rodr(?)guez-L(?)pez J N， Garc(?)a-Sevilla F et al．Analysis and interpretation of the action mechanism of mushroom tyrosinase on monophenols and diphenols generating highly unstableo-quinones [J]．Biochimica et BiophyicaActa， 2001，1548： 1-22．
[50]Mary S R， Manuel R．Specific Tyrosinases Associated with Melanoma Replicative Senescence and Melanogenesis[J]．CANCER RESEARCH， 1993， 53(1)： 2469-2471．
[51] Ling H, Heinz A, William JP. Interspecies difference in the regulation of melanocyte development by SOX10 and MITF [J]. PNAS, 2006, 103(24): 9081-9085.
[52] Akiha K, Mayuko K, Akir S, et al. Mitf contributes to melanosome distribution and melanophore dendricity[J]. Pigment Cell Melanoma Res, 2007, 21: 56-62.
[53] Toshihiko H, Jacqueline M, Wilfred D, et al. The Repeat Domain of the Melanosomal Matrix Protein PMEL17/GP100 Is Required for the Formation of Organellar Fibers[J]. J. Biol. Chem, 2006, 281(30): 21198-21208.
[54] Yuji Y, Michaela B, Vincent JH, the Regulation of Skin Pigmentationo[J]. J. Biol Chem, 2007, 282(38): 27557-27561.
[55] Douglas MM, Seema G, and Lee B. Characterization of an ERK-binding Domain in Microphthalmia-associated Transcription Factor and Differential Inhibition of ERK2-mediatedSubstrate Phosphorylation [J]. J. Biol. Chem, 2005, 280(51): 42051-42060.
[56] Zalfa A. A, Ana L K, Renny J. K. Melanoma prevention strategy based on using tetrapeptide α -MSH analogs that protect human melanocytes from UV-induced DNA damage and cytotoxicity [J]. FASEB J, 2006, 20: 888-896.
[57] Gertrude-E. C, Vincent JH. Human skin pigmentation: melanocytes modulate skin color in response to stress [J]. FASEB J, 2007, 21: 976-994.
[58] Roser B, Robert B. Cyclic AMP a Key Messenger in the Regulation of Skin Pigmentation [J]. PIGMENT CELL RES, 2000, 13: 60-69.
[59] Kazuo K, Steven JO, Rene G. Microphthalmia Transcription Factor as a Molecular Marker for Circulating Tumor Cell Detection in Blood of Melanoma Patients [J]. Clin Cancer Res 2006, 12(4): 1137-1143.
[60] Chen YM, Walter C. Melanogenesis in Human Melanomas [J]. Cancer Res 1975, 35: 606-612.
[61] Nicolas D, Robert H, Jan M, et al. In Melanoma, RAS Mutations Are Accompanied by Switching Signaling from BRAF to CRAF and Disrupted Cyclic AMP Signaling [J]. Cancer Res 2006, 66 (19): 9483-9491.
[62] Mary SR, Manuel R. Specific Tyrosinases Associated with Melanoma Replicative Senescence and Melanogenesis [J]. Cancer Res, 1993, 53: 2469-2471.
[63] Genji I, Yutaka M. Loss of Melanogenic Properties in Tyrosinases Induced by Glycosylation Inhibitors within Malignant Melanoma Cells [J]. Cancer Res, 1982, 42: 1994-2002.
[64] Kowichi J, Yasuhiro M, Koichi H, et al. Characterization of Melanogenesis and Morphogenesis of Melanosomes by Physicochemical Properties of Melanin and Melanosomes in Malignant Melanoma [J]. Cancer Res, 1984, 44: 1128-1134.
[65] Sungbin I, Osamu M, Fuping P, et al. Activation of the Cyclic AMP Pathway by a-Melanotropin Mediates the Response of Human Melanocytes to Ultraviolet B Radiation [J]. Cancer Res, 1998, 58: 47-54.
[66] Solano F, Briganti S, Picardo M, et al. Hypopigmenting agents: an updated review on biological, chemical and clinical aspects [J]. Pigment Cell Res., 2006, 19: 550-571.
[67] Park H Y, Wu C, Yonemoto L, et al. MITF mediates cAMP-induced protein kinase C-beta expression in human melanocytes [J]. Biochem. J., 2006, 395(3): 571-578.
[68] Lee J, Jung E, Park J, et al. Glycyrrhizin induces melanogenesis by elevating a cAMP level in b16 melanoma cells [J]. J. Invest. Dermatol., 2005, 124(2): 405-411.
[69] Yang JY, Koo JH, Song YG, et al. Stimulation of melanogenesis by scoparone in B16 melanoma cells [J]. Acta Pharmacol. Sin., 2006, 27(11): 1467-1473.
[70] Lin CB, Babiarz L, Liebel F, et al. Modulation of microphthalmia-associated transcription factor gene expression alters skin pigmentation [J]. J. Invest. Dermatol., 2002, 119: 1330-1340.
[71] Kim KS, Kim JA, Eom SY, et al. Inhibitory effect of piperlonguminine on melanin production in melanoma B16 cell line by downregulation of tyrosinase expression [J]. Pigment Cell Res., 2006, 19(1): 90-98.
[72] Saito H, Yasumoto K, Takeda K, et al. Microphthalmia-associated transcription factor in the Wnt signaling pathway [J]. Pigment Cell Res., 2003, 16(3): 261-265.
[73] Perez-Bernal A, Munoz-Perez MA, Camacho F. Management of facial hyperpigmentation [J]. American Journal of Clinical Dermatology, 2000, 1(5): 261-268.
[74] Victor FC, Gelber J, Rao B. Melasma: a review [J]. Journal of Cutaneous Medicine and Surgery, 2004, 8(2): 97-102. Perez-Bernal A, Munoz-Perez M A, Camacho F. Management of facial hyperpigmentation [J]. Am. J. Clin. Dermatol., 2000, 1(5): 261-268.
[75]Briganti S， Camera E， Picardo M．Chemical and instrumental approaches to treat hyperpigmentation [J]．Pigment Cell Res．， 2003， 16(2)： 101-110．
[76]Sayre LM， Smith MA， Perry G．Chemistry and biochemistry of oxidative stress in neurodegenerative disease[J]．Curr．Chem．， 2001， 8： 721-738．
[77]Kikuchi A， Takeda A， Onodera H， et al．Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy[J]．Neurobiol．Dis．， 2002， 9： 244-248．
[78]Jenner P．Oxidative stress in Parkinson's disease[J]．Ann．Neurol， 2003， 53： S26-S36．
[79]Ben-Shachar D， Zuk R， Glmka Y．Dopamine neurotoxicity： inhibition of mitochondrial respiration[J]．J．Neurochem．1995， 64： 718-723．
[80]Smythies J， Galzigna L．The oxidative metabolism of catecholamines in the brain： a review[J]．Biochim．Biophys．Acta．， 1998， 1380： 159-162．
[81]Xu Y， Stokes AH， Roskoski R， et al．Dopamine， in the presence of tyrosinase， covalently modifies and inactivates tyrosine hydroxylase[J]．J．Neurosci．Res．， 1998， 54： 691-697．
[82]Stokes A H， Hastings T G， Vrana KE．Cytotoxic and genotoxic potential of dopamine[J]．J．Neurosci．Res．1999， 55： 659-665．
[83]Cavalieri EL， Li KM， Balu N， et al．Catechol ortho-quinones： the electrophilic compounds thatformdepurinatingDNAadductsandcouldinitiatecancerandother diseases[J]．Carcinogenesis， 2002， 23： 1071-1077．
[84]Bolton．2000 Bolton J L， Trush M A， et al．Role of quinones in toxicology[J]．Chem．Res．Toxicol．， 2000， 13： 135-160．
[85]Polymeropoulos MH， Lavedan C， Leroy E， et al．Mutation in the alpha-synuclein gene identified in families with Parkinson's disease[J]．Science， 1997， 276： 2045-2047．
[86]Conway KA， Rochet JC， Bieganski RM， et al．Kinetic stabilization of the alpha-synuclein protofibril by a dopamine-alpha-synuclein adduct[J]．Science， 2001，294： 1346-1349．
[87]李小迪．色素沉着与美白护肤品[J]．香料香精化妆品， 2002， 1：29-31．
[88]刘宇红，董银卯，李才广．皮肤化学美白剂抑制酪氨酸酶活性的研究[J]．日用化学工业，2001，31(1)：21-23．
[89]芮斌，蒋惠亮，淘文沂．美白添加剂—曲酸衍生物[J]．精细与专用化学品，2002， 9：13-14．
[90] 蒋人俊, 汤智 凌, 殷雷等. 美白化妆品的研制[J] 。中外轻工科技, 1998,3:3-5.
[91] Laveda F, Nunez-Delicado E, Garcia-Carmona F, et al. Proteolytic activation of latent Paraguaya peach PPO. Characterization of monophenolase activity [J]. J. Agric. Food Chem., 2001, 49(2): 1003-1008.
[92] Chisari M, Barbagallo RN, Spagna G. Characterization of polyphenol oxidase and peroxidase and influence on browning of cold stored strawberry fruit [J]. J. Agric. Food Chem., 2007, 55(9): 3469-3476.
[93] Spagna G, Barbagallo RN, Chisari M, et al. Characterization of a tomato polyphenol oxidase and its role in browning and lycopene content [J]. J. Agric. Food Chem., 2005, 53(6): 2032-2038.
[94] Busch JM. Enzymic browning in potatoes: a simple assay for a polyphenol oxidase catalysed reaction [J]. Biochemical Education, 1999, 27: 171-173.
[95] Jiang YM, Duan XW, Joyce D, et al. Advances in understanding of enzymatic browning in harvested litchi fruit [J]. Food Chemistry, 2004, 88: 443-446.
[96] Soliva R C, Elez P, Sebastian M, et al. Evaluation of browning effect on avocado puree preserved by combined methods [J]. Innovative Food Science & Emerging Technologies, 2001, 1:261-268.
[97] Murata M, Nishimura M, Murai N, et al. A transgenic apple callus showing reduced polyphenol oxidase activity and lower browning potential [J]. Biosci. Biotechnol. Biochem., 2001, 65(2): 383-388.
[98] Kessler J C, Rochet J C , Lansbury P T. The N-terminal repeatdomain of alpha-synuclein inhbits beta-sheet and amyloid fibrilformation [J]. Biochemistry, 2003, 42 (3): 672-678.
[99] Maroteaux L, Campanelli, J T, SchellerRH. Synuclein: A neuron-specific protein localized to the nucleus and presynaptic nerve terminal[J]. J.Neurosci., 1988, 8: 2804-2815.
[100] Maroteaux, L and Scheller, R H. The rat brain synucleins; family of proteins transiently associated with neuronal membrane[J]. Mol. Brain Res. 1991(11): 335-343.
[101] Tobe T, Nakajo S, Tanaka A, et al. Cloning and characterization of the cDNA encoding a novel specific 14-kDa protein[J]. J. Neurochem. 1992(59): 1624-1629.
[102] U(?)da, K, Fukushima, H, Masliah, E, et al. Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease[J]. Proc. Natl. Acad. Sci., 1993, 90(11): 282-286.
[103] Bayer, TA, Jakala, P, Hartmann, T, et al. a-Synuclein accumulates in Lewy bodies in Parkinson's disease and dementia with Lewy bodies but not in Alzheimer's disease P-amyloid cores[J]. Neurosci. Lett. 1999, 266: 213-216.
[104] Culvenor, JG, McLean, CA, Cutt, S, et al. Non-Ap component of Alzheimer's disease amyloid (NAC)revisited. NAC and a-synuclein are not associated with Aβ amyloid[J]. Am. J.Pathol. 1999(155): 1173-1881.
[105] Jakes, R, Spillantini, MG, Goedert, M. Identification of two distinct synucleins from human brain[J]. FEBS Lett. 1994(345): 27-32.
[106] George, J M, Jin, H, Woods, et al. Characterization of a novel protein regulated during the critical period for song learning in the zebra finch[J]. Neuron, 1995, 15: 361-372.
[107] M. M. Mouradian, edited. Methods in Molecular Medicine, Parkinson's Disease: Methods and Protocols, Humana Press Inc, Totowa, NJ, vol. 62: 36.
[108] Weinreb, PH, Zhen, W, Poon, AW, et al. NACP, a protein implicated in Alzheimer's disease and learning, is natively unfolded[J]. Biochemistry, 996(35): 13709-13715.
[109] Moore, DJ,West AB, DawsonVL, et al. Molecular pathophysiology of Parkinson's disease Rev[J]. Neurosci. 2005(28): 57-87.
[110] Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies[J]. Nature 1997,388:839-840.
[111] Lewy, F. H. Paralysis agitans. I. Pathologische Anatomie, in Handbuch der Neurologie, 1912(3) (Lewandowsky, M. and Abelsdorff, G., eds.), Springer,Berlin, pp. 920-933.
[112] Tretiakoff, M. C. (1919) Thesis, University of Paris. [113] Golbe LI, Di Iorio G, BonavitaV,et al. A large kindred with autosomal dominant Parkinson's disease[J]. Ann.Neurol. 1990, 27: 276-282.
[114] Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinson's disease to chromosome 4q21-q23[J]. Science, 1996,274: 1197-1199.
[115] Athanassiadou A, VoutsinasG, Psiouri L, et al. Genetic analysis of families with Parkinson disease that carry the Ala53Thr mutation in the gene encoding a-synuclein[J]. Am. J. Hum. Genet. 1999,65:555-558.
[116] Polymeropoulos MH, Lavedan C, Leroy E, et al. Mutation in the a-synuclein gene identified in families with Parkinson's disease[J]. Science 1997, 276: 2045-2047.
[117] Gao HM,Paul TK,Kunihiro U, et al. Neuroinflammation and Oxidation/Nitration of α-Synuclein Linked to Dopaminergic Neurodegeneration[J]. Neurobiology of Disease, 2008, 28(30): 7687-7698.
[118] Magali P,Tudor F,Liisa M, et al. Aggregated α-SynucleinMediates Dopaminergic Neurotoxicity In Vivo[J]. Neurobiology of Disease, 2007, 27(12): 3338-3346.
[119] Brian MD, Lisa RW, Sheng TH, et al. Calpain-Cleavage of α-Synuclein Connecting roteolytic Processing to Disease-Linked Aggregation[J]. Neurobiology, 2007, 170(5): 1725-1738.
[120] Eliezer M, Edward R, Anthony A, et al. Effects of a-Synuclein Immunization in a Mouse Model of Parkinson's Disease[J]. Neuron, 2005, 46: 857-868.
[121] Jochen K, Youngah S, Eliezer M, et al. Hsp70 Reducesa-Synuclein Aggregation and Toxicity[J]. The Journal of Biological Chemistry 2004, 279(24): 25497-25502.
[122] Abeliovich A, Schmitz Y, Farin I, et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system[J]. Neuron, 2000, 25: 239-252.
[123] Chen L, Feany MB. Alpha-synuclein phosphorylation controls neurotoxicity and inclusion formation in a Drosophila model of Parkinson disease[J]. Nat Neurosci, 2005, 8: 657-663.
[124] Chu Y, Kordower JH. Age-associated increases of alpha-synuclein in monkeys and humans are associated with nigrostriatal dopamine depletion: is this the target for Parkinson's disease? [J]. Neurobiol Dis, 2007, 25: 134-149.
[125] Singleton AB, FarrerM, Johnson J, et al. alpha-Synuclein locus triplication causes Parkinson's disease[J]. Science, 2003, 302: 841.
[126] Spillantini MG, Schmidt ML, Lee VM, et al. Alpha-synuclein in Lewy bodies[J]. Nature, 1997,388:839-840.
[127] Masliah E, Rockenstein E, Veinbergs I, et al. Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders[J]. Science, 2000,287: 1265-1269.
[128] Richter-Landsberg C, Gorath M, Trojanowski JQ, et al. alpha-synuclein is developmentally expressed in cultured rat brain oligodendrocytes[J]. J Neurosci Res, 2006, 2: 9-14.
[129] Smith WW, Margolis RL, Li X, et al. Alpha-synuclein phosphorylation enhances eosinophilic cytoplasmic inclusion formation in SH-SY5Y cells[J]. J Neurosci., 2005, 25: 5544-5552.
[130] Tofaris GK, Garcia RP, Humby T, et al. Pathological changes in dopaminergic nerve cells of the substantia nigra and olfactory bulb in mice transgenic for truncated human alpha-synuclein(1-120): implications for Lewy body disorders[J]. J Neurosci., 2006, 26: 3942-3950.
[131] Uryu K, Richter-Landsberg C, Welch W, et al. Convergence of heat shock protein 90 with ubiquitin in filamentous alpha-synuclein inclusions of alpha-synucleinopathies[J]. Am J Pathol, 2006, 168:947-9131.
[132] Zhang W, Wang T, Pei Z, et al. Aggregated alpha-synuclein activates microglia: a process leading to disease progression in Parkinson's disease[J]. FASEB J. 2005, 19: 533-542
[133] Takafumi H, Michiko MK, Atsushi T, et al. a-Synuclein facilitates the toxicity of oxidized catechol metabolites: Implications for selective neurodegeneration in Parkinson's disease[J]. FEBS Letters, 2006, 580: 2147-2152.
[134] Hasegawa T, Matsuzaki-Kobayashi M, Takeda A, et al. Alpha-synuclein facilitates the toxicity of oxidized catechol metabolites: implications for selective neurodegeneration in Parkinson's disease[J]. FEBS Lett. 2006, 580: 2147-2152.
[135] Isabella T, Marco B, Francesco V, et al. The Reaction of α -Synuclein with Tyrosinase possible implications for parkinson disease[J]. The Journal of Biological Chemistry, 2008, 283(24): 16808-16817.
[136] P. P. Kumar, R. Paramashivappa, P. J. Vithayathil, et al. Process for Isolation of Cardanol from Technical Cashew (Anacardium occidentale L.) Nut Shell Liquid. J. Agric. Food. Chem. 2002, 50: 4705-4708.