Dokument: Photoprotektive Effekte von β-Carotin, Melanin, Vitamin C und Vitamin E auf Protoporphyrin IX-induzierte phototoxische Reaktionen im Photo-Hen's-Egg-Test
| Titel: | Photoprotektive Effekte von β-Carotin, Melanin, Vitamin C und Vitamin E auf Protoporphyrin IX-induzierte phototoxische Reaktionen im Photo-Hen's-Egg-Test | |||||||
| Weiterer Titel: | Photo protective effects of β-Carotene, Melanin, Vitamin C and Vitamin E against protoporphyrin-IX induced phototoxicity in the Photo-Hen's-Egg-Test | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=44777 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20180201-151710-7 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Deutsch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Dr. Bafteh, Pascal [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kruse, Roland [Gutachter] Prof. Dr. med. Fenk, Roland [Gutachter] | |||||||
| Stichwörter: | Erythropoetische Protoporphyrie, Phototoxizität, PHET, β-Carotin, Melanin, Vitamin C, Vitamin E, MSH-Analaga | |||||||
| Dewey Dezimal-Klassifikation: | 600 Technik, Medizin, angewandte Wissenschaften » 610 Medizin und Gesundheit | |||||||
| Beschreibungen: | Bei der Erythropoetischen Protoporphyrie handelt es sich um eine sehr seltene, genetisch bedingte Stoffwechselstörung im blutbildenden System, bei der vermehrt Protoporphyrine in Blut, Erythrozyten und Gewebe abgelagert werden. Dies führt zum ersten klinischen Symptom, der vermehrten Photosensibilität. Ursächlich ist die gestörte Funktion bzw. der Funktionsausfall der Ferrochelatase. Die Prognose hängt in erster Linie vom Grad der Leberbeteiligung ab. Aufgrund der schwerwiegenden Einschränkungen – insbesondere durch die Vermeidung von Lichtexposition – werden Alltag und Lebensqualität der Patienten und ihrer Familien stark beeinflusst.
Ein Therapieansatz besteht in der topischen bzw. systemischen Gabe der Antioxidantien Ascorbinsäure, β-Carotin und Vitamin E. Zusätzlich steht das α-MSH-Analogon Afamelanotid, das unter anderem die körpereigene Melaninbildung erhöhen/anregen soll, im Fokus aktueller Studien. In der vorliegenden Arbeit wurde mithilfe des PHET zunächst die phototoxische Wirkung von UV-B-Strahlung sowie von Protoporphyrin IX in Kombination mit UV-A-Strahlung evaluiert. Im zweiten Schritt wurden durch die zusätzliche Gabe der oben genannten Antioxidantien und Melanin photoprotektive Potentiale ermittelt. Die Ergebnisse wurden mithilfe der Parameter Letalität, Membraneintrübungen und Hämorrhagien am Dottersack-Gefäßsystem protokolliert. Die vorliegenden Testergebnisse zeigen für die Substanzen Ascorbinsäure, β-Carotin und VitaminE eine signifikante Minderung von UV-B-induzierten Schäden am Dottersack- Gefäßsystem. Gegenüber Protoporphyrin-IX-induzierter Phototoxizität konnte jedoch nur ein mäßiger photoprotektiver Effekt registriert werden. Melanin zeigte gegenüber UV-B- sowie Protoporphyrin-IX-induzierten Schäden einen signifikanten Schutzeffekt. Dies deutet darauf hin, dass ein durch Afamelanotid erhöhter Melanin-Gehalt in der Haut ebenfalls einen vielversprechenden Effekt aufweisen könnte. Nach unseren Ergebnissen könnte Afamelanotid für lichtempfindliche Patienten eine neue Therapieoption darstellen. Außerdem liegt die Annahme nahe, dass Ascorbinsäure, β-Carotin und VitaminE unter Heranziehung aktueller Patientenstudien zur Therapie der EPP bestenfalls supportiv geeignet sind.The aim of our study was to evaluate the photoprotective potential of β-carotene, ascorbic acid, vitamin e and melanin against protoporphyrine IX-induced phototoxicity via photo hen's egg test. In three independent test groups, the yolk sac blood vessel system of hen's eggs was exposed to protoporphyrine IX and irradiated with ultraviolet A (UVA). The groups separately also received β-carotene, ascorbic acid, vitamin e and melanin to investigate their photoprotective capacity. Morphological changes and embryo lethality were recorded in these test groups for a period of 24 h. The same parameters were obtained in the different control groups. The control groups exhibited only minimal morphological changes and no fatalities. In contrast, severe phototoxic damage and a high lethality rate (75%) were observed in the test group exposed to protoporphyrine IX and UVA. Lethality was e.g. somewhat lower in the β-carotene test group (58%) and was considerably lower in the melanin test group (17%). The photoprotective potential against protoporphyrine IX-induced phototoxic damage was moderate for β-carotene and was remarkable for melanin. Given that synthetic melanocyte stimulating hormone (MSH) analogues induce a de novo synthesis of melanin without any previous ultraviolet irradiation in human skin, the application of MSH analogues might be conceived of as 'light hardening' without light. Synthetic MSH analogues thus may represent a new promising therapeutic option for photodermatoses especially for erythropoietic protoporphyria. | |||||||
| Quelle: | 1. Puy H, Gouya L, Deybach J-C. Porphyrias. Lancet. 2010;375(9718):924–37.
2. Frank J, Poblete-Gutiérrez P. Hereditary metabolic diseases with cutaneous manifestations : An update. Hautarzt. 2011;62(2):98–106. 3. Gouya L, Puy H, Robreau A-M, Bourgeois M, Lamoril J, Da Silva V, u. a. The penetrance of dominant erythropoietic protoporphyria is modulated by expression of wildtype FECH. Nat Genet. 2002;30(1):27–8. 4. Frank J, Poblete-Gutiérrez P. Delayed diagnosis and diminished quality of life in erythropoietic protoporphyria: results of a cross-sectional study in Sweden. J Intern Med. 2011;269(3):270–4. 5. Nakamura T, Saito M, Shimada Y, Fukaya H, Shida Y, Tokuji Y. Induction of aminolevulinic acid synthase gene expression and enhancement of metabolite, protoporphyrin IX, excretion by organic germanium. Eur J Pharmacol. 25. 2011;653(1- 3):75–81. 6. Stölzel U, Stauch T, Doss MO. Porphyrias. Internist. 2010;51(12):1525–33. 7. Van Serooskerken A-M van T, Poblete-Gutiérrez P, Frank J. The porphyrias: clinic, diagnostics, novel investigative tools and evolving molecular therapeutic strategies. Skin Pharmacol Physiol. 2010;23(1):18–28. 8. Casanova-González MJ, Trapero-Marugán M, Jones EA, Moreno-Otero R. Liver disease and erythropoietic protoporphyria: a concise review. World J Gastroenterol WJG. 2010;16(36):4526–31. 9. Minder EI, Schneider-Yin X, Steurer J, Bachmann LM. A systematic review of treatment options for dermal photosensitivity in erythropoietic protoporphyria. Cell Mol Biol Noisy-- Gd Fr. 2009;55(1):84–97. 10. Mathews-Roth MM, Pathak MA, Fitzpatrick TB, Harber LH, Kass EH. Beta carotene therapy for erythropoietic protoporphyria and other photosensitivity diseases. Arch Dermatol. 1977;113(9):1229–32. 11. Stahl W, Sies H. Carotenoids and protection against solar UV radiation. Skin Pharmacol Appl Skin Physiol. 2002;15(5):291–6. 12. Bayerl C. Beta-carotene in dermatology: Does it help? Acta Dermatovenerol Alp Panon Adriat. 2008;17(4):160–2, 164–6. 13. Kobza A, Ramsay CA, Magnus IA. Oral carotene therapy in actinic reticuloid and solar urticaria. Failure to demonstrate a photoprotective effect against long wave ultraviolet and visible radiation. Br J Dermatol. 1973;88(2):157–66. 70 14. Wennersten G. Carotenoid treatment for light sensitivity: a reappraisal and six years’ experience. Acta Derm Venereol. 1980;60(3):251–5. 15. Mathews-Roth MM, Pathak UA, Fitzpatrick TB, Harber LC, Kass EH. Beta-carotene as an oral photoprotective agent in erythropoietic protoporphyria. JAMA J Am Med Assoc. 1974;228(8):1004–8. 16. Lecluse ALY, Kuck-Koot VCM, van Weelden H, Sigurdsson V, Russel IM, Frank J, u. a. Erythropoietic protoporphyria without skin symptoms-you do not always see what they feel. Eur J Pediatr. 2008;167(6):703–6. 17. Roelandts R. Photo(chemo)therapy and general management of erythropoietic protoporphyria. Dermatol Basel Switz. 1995;190(4):330–1. 18. Plewig G, Hofmann C, Braun-Falco O, Nath G, Kreitmair A. A new apparatus for the delivery of high intensity UVA and UVA+UVB irradiation, and some dermatological applications. Br J Dermatol. 1978;98(1):15–24. 19. Neumann NJ, Hanneken S, Ruzicka T, Lehmann P. Phototoxicity of exogenous protoporphyrin IX and delta-aminolevulinic acid in the photo hen’s egg test. Photodermatol Photoimmunol Photomed. 2004;20(5):224–9. 20. Neumann NJ, Hölzle E, Lehmann P, Rosenbruch M, Klaucic A, Plewig G. Photo hen’s egg test: a model for phototoxicity. Br J Dermatol.1997;136(3):326–30. 21. Neumann NJ, Hölzle E, Wallerand M, Vierbaum S, Ruzicka T, Lehmann P. The photoprotective effect of ascorbic acid, acetylsalicylic acid, and indomethacin evaluated by the photo hen’s egg test. Photodermatol Photoimmunol Photomed. 1999;15(5):166–70. 22. Harms J, Lautenschlager S, Minder CE, Minder EI. An alpha-melanocyte-stimulating hormone analogue in erythropoietic protoporphyria. N Engl J Med. 2009;360(3):306–7. 23. Layer G, Reichelt J, Jahn D, Heinz DW. Structure and function of enzymes in heme biosynthesis. Protein Sci Publ Protein Soc. 2010;19(6):1137–61. 24. Kosenow W, Treibs A. Light hypersensitivity and porphyrinemia. Z Für Kinderheilkd. 1953;73(1):82–92. 25. Michaels BD, Del Rosso JQ, Mobini N, Michaels JR. Erythropoietic protoporphyria: a case report and literature review. J Clin Aesthetic Dermatol. 2010;3(7):44–8. 26. Todd DJ. Erythropoietic protoporphyria. Br J Dermatol. 1994;131(6):751–66. 27. Kennedy JC, Pottier RH, Pross DC. Photodynamic therapy with endogenous protoporphyrin: IX: Basic principles and present clinical experience. J Photochem Photobiol B. 1990;6(1–2):143–8. 28. Szeimies R-M, Calzavara-Pinton P, Karrer S, Ortel B, Landthaler M. Topical photodynamic therapy in dermatology. J Photochem Photobiol B. 1996;36(2):213–9. 71 29. Piomelli S, Lamola AA, Poh-Fitzpatrick MF, Seaman C, Harber LC. Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro. J Clin Invest. 1975;56(6):1519–27. 30. Brun A, Western A, Malik Z, Sandberg S. Erythropoietic protoporphyria: photodynamic transfer of protoporphyrin from intact erythrocytes to other cells. Photochem Photobiol. 1990;51(5):573–7. 31. Afonso SG, Enríquez de Salamanca R, Batlle AM. The photodynamic and non- photodynamic actions of porphyrins. Braz J Med Biol Res Rev Bras Pesqui Médicas E Biológicas Soc Bras Biofísica Al. 1999;32(3):255–66. 32. Ibrahim GW, Watson CJ. Enterohepatic circulation and conversion of protoporphyrin to bile pigment in man. Proc Soc Exp Biol Med Soc Exp Biol Med N Y N. 1968;127(3):890– 5. 33. Ogilby PR. Singlet oxygen: there is indeed something new under the sun. Chem Soc Rev. 2010;39(8):3181–209. 34. Liu B, Farrell TJ, Patterson MS. A dynamic model for ALA-PDT of skin: simulation of temporal and spatial distributions of ground-state oxygen, photosensitizer and singlet oxygen. Phys Med Biol. 2010;55(19):5913–32. 35. Goldstein BD, Harber LC. Erythropoietic protoporphyria: lipid peroxidation and red cell membrane damage associated with photohemolysis. J Clin Invest. 1972;51(4):892–902. 36. Bagdonas S, Ma LW, Iani V, Rotomskis R, Juzenas P, Moan J. Phototransformations of 5- aminolevulinic acid-induced protoporphyrin IX in vitro: a spectroscopic study. Photochem Photobiol. 2000;72(2):186–92. 37. Yano S, Hirohara S, Obata M, Hagiya Y, Ogura S, Ikeda A, u. a. Current states and future views in photodynamic therapy. J Photochem Photobiol C Photochem Rev. 2011;12(1):46–67. 38. Tegos G, Dai T, Fuchs BB, Coleman JJ, Prates RA, Astrakas C, u. a. Concepts and principles of photodynamic therapy as an alternative antifungal discovery platform. Fungi Their Interact. 2012;3:120. 39. Kim CH, Chung C-W, Choi KH, Yoo J-J, Kim DH, Jeong Y-I, u. a. Effect of 5- aminolevulinic acid-based photodynamic therapy via reactive oxygen species in human cholangiocarcinoma cells. Int J Nanomedicine. 2011;6:1357–63. 40. Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky KE, u. a. 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer. 1997;79(12):2282–308. 72 41. Kennedy JC, Marcus SL, Pottier RH. Photodynamic therapy (PDT) and photodiagnosis (PD) using endogenous photosensitization induced by 5-aminolevulinic acid (ALA): mechanisms and clinical results. J Clin Laser Med Surg. 996;14(5):289–304. 42. Lim HW. Mechanisms of phototoxicity in porphyria cutanea tarda and erythropoietic protoporphyria. Immunol Ser. 1989;46:671–85. 43. Schnait FG, Wolff K, Konrad K. Erythropoietic protoprophyria--submicroscopic events during the acute photosensitivity flare. Br J Dermatol. 1975;92(5):545–57. 44. Fuchs J. Potentials and limitations of the natural antioxidants RRR-alpha-tocopherol, L- ascorbic acid and beta-carotene in cutaneous photoprotection. Free Radic Biol Med. 1998;25(7):848–73. 45. Frank J, Poblete-Gutiérrez P. Valuable insights from molecular genetic studies in the porphyrias. Br J Dermatol. 2010;162(3):470–1. 46. Lecha M. Erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. 2003;19(3):142–6. 47. Neumann NJ, Lehmann P. Photodermatosen. Ein Leitfaden zur Diagnostik. 1. Aufl. Steinkopff-Verlag Darmstadt; 2000. 48. Wahlin S, Srikanthan N, Hamre B, Harper P, Brun A. Protection from phototoxic injury during surgery and endoscopy in erythropoietic protoporphyria. Liver Transplant Off Publ Am Assoc Study Liver Dis Int Liver Transplant Soc. 2008;14(9):1340–6. 49. Diffey BL, Farr PM. Sunscreen protection against UVB, UVA and blue light: an in vivo and in vitro comparison. Br J Dermatol. 1991;124(3):258–63. 50. Rosen CF. Topical and systemic photoprotection. Dermatol Ther. 2003;16(1):8–15. 51. Spelt JMC, de Rooij FWM, Wilson JHP, Zandbergen AAM. Vitamin D deficiency in patients with erythropoietic protoporphyria. J Inherit Metab Dis. 2010;33 Suppl 3:S1–4. 52. Yoo DJ, Lee HC, Yu E, Jin YJ, Shim JH, Kim KM, u. a. Cholestyramine resin for erythropoietic protoporphyria with severe hepatic disease: a case report. Korean J Hepatol. 2010;16(1):83–8. 53. Boffa MJ, Ead RD, Reed P, Weinkove C. A double-blind, placebo-controlled, crossover trial of oral vitamin C in erythropoietic protoporphyria. Photodermatol Photoimmunol Photomed. 1996;12(1):27–30. 54. Johnson JA, Fusaro RM. Possible use of vitamins C and-or E in erythropoietic protoporphyria. JAMA J Am Med Assoc. 1973;224(6):901–2. 55. Dreher F, Maibach H. Protective effects of topical antioxidants in humans. Curr Probl Dermatol. 2001;29:157–64. 73 56. Warren LJ, George S. Erythropoietic protoporphyria treated with narrow-band (TL-01) UVB phototherapy. Australas J Dermatol. 1998;39(3):179–82. 57. Murphy GM, Hawk JLM. Erythropoietic protoporphyria advances today, with a special tribute to the late Professor Ian Magnus. Br J Dermatol. 2006;155(3):501–3. 58. Collins P, Ferguson J. Narrow-band UVB (TL-01) phototherapy: an effective preventative treatment for the photodermatoses. Br J Dermatol. 1995;132(6):956–63. 59. Nowis D, Makowski M, Stokłosa T, Legat M, Issat T, Gołab J. Direct tumor damage mechanisms of photodynamic therapy. Acta Biochim Pol. 2005;52(2):339–52. 60. Tyrrell J, Campbell SM, Curnow A. The effect of air cooling pain relief on protoporphyrin IX photobleaching and clinical efficacy during dermatological photodynamic therapy. J Photochem Photobiol B. 2011;103(1):1–7. 61. Epstein JH. Phototoxicity and photoallergy. Semin Cutan Med Surg. 1999;18(4):274–84. 62. Nigen S, Knowles SR, Shear NH. Drug eruptions: approaching the diagnosis of drug- induced skin diseases. J Drugs Dermatol JDD. 2003;2(3):278–99. 63. Sohal RS, Weindruch R. Oxidative stress, caloric restriction, and aging. Science. 1996;273(5271):59–63. 64. Darr D, Fridovich I. Free radicals in cutaneous biology. J Invest Dermatol. 1994;102(5):671–5. 65. Pospíšil P. Molecular mechanisms of production and scavenging of reactive oxygen species by photosystem II. Biochim Biophys Acta. 2012;1817(1):218-31 66. Stahl W, Sies H. Physical quenching of singlet oxygen and cis-trans isomerization of carotenoids. Ann N Y Acad Sci. 1993;691:10–9. 67. Seifried HE, Anderson DE, Fisher EI, Milner JA. A review of the interaction among dietary antioxidants and reactive oxygen species. J Nutr Biochem. 2007;18(9):567–79. 68. Sies H. Oxidative stress: oxidants and antioxidants. Exp Physiol. 1997;82(2):291–5. 69. Maeda Y, Inoguchi T. [Oxidative stress]. Nihon Rinsho Jpn J Clin Med. 2010;68(5):814–8. 70. Müller T, Muhlack S. Cysteinyl-glycine reduction as marker for levodopa-induced oxidative stress in Parkinson’s disease patients. Mov Disord Off J Mov Disord Soc. 2011;26(3):543–6. 71. Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010;107(9):1058–70. 72. Sawyer DB. Oxidative stress in heart failure: what are we missing? Am J Med Sci. 2011;342(2):120–4. 74 73. Kryston TB, Georgiev AB, Pissis P, Georgakilas AG. Role of oxidative stress and DNA damage in human carcinogenesis. Mutat Res. 2011;711(1-2):193–201. 74. Halliwell B. Antioxidant defence mechanisms: from the beginning to the end (of the beginning). Free Radic Res. 1999;31(4):261–72. 75. Willcox JK, Ash SL, Catignani GL. Antioxidants and prevention of chronic disease. Crit Rev Food Sci Nutr. 2004;44(4):275–95. 76. Dolashka-Angelova P, Angelova M, Genova L, Stoeva S, Voelter W. A novel Cu,Zn superoxide dismutase from the fungal strain Humicola lutea 110: isolation and physico- chemical characterization. Spectrochim Acta A Mol Biomol Spectrosc. 1999;55A(11):2249–60. 77. Zamocky M, Furtmüller PG, Obinger C. Evolution of catalases from bacteria to humans. Antioxid Redox Signal. 2008;10(9):1527–48. 78. Harington CR, Mead TH. Synthesis of glutathione. Biochem J. 1935;29(7):1602–11. 79. Aslund F, Berndt KD, Holmgren A. Redox potentials of glutaredoxins and other thiol- disulfide oxidoreductases of the thioredoxin superfamily determined by direct protein- protein redox equilibria. J Biol Chem. 1997;272(49):30780–6. 80. Chen L, Hu JY, Wang SQ. The role of antioxidants in photoprotection: A critical review. J Am Acad Dermatol. 2012;67(5):1013–24. 81. McCall MR, Frei B. Can antioxidant vitamins materially reduce oxidative damage in humans? Free Radic Biol Med. 1999;26(7-8):1034–53. 82. Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1–40. 83. Sies H, Stahl W, Sevanian A. Nutritional, dietary and postprandial oxidative stress. J Nutr. 2005;135(5):969–72. 84. Ochiai Y, Kaburagi S, Obayashi K, Ujiie N, Hashimoto S, Okano Y, u. a. A new lipophilic pro-vitamin C, tetra-isopalmitoyl ascorbic acid (VC-IP), prevents UV-induced skin pigmentation through its anti-oxidative properties. J Dermatol Sci. 2006;44(1):37–44. 85. Mandl J, Szarka A, Bánhegyi G. Vitamin C: update on physiology and pharmacology. Br J Pharmacol. 2009;157(7):1097–110. 86. Myllylä R, Majamaa K, Günzler V, Hanauske-Abel HM, Kivirikko KI. Ascorbate is consumed stoichiometrically in the uncoupled reactions catalyzed by prolyl 4-hydroxylase and lysyl hydroxylase. J Biol Chem. 1984;259(9):5403–5. 87. Hurrell R, Egli I. Iron bioavailability and dietary reference values. Am J Clin Nutr. 2010;91(5):1461S – 1467S. 75 88. Heller R, Unbehaun A, Schellenberg B, Mayer B, Werner-Felmayer G, Werner ER. L- ascorbic acid potentiates endothelial nitric oxide synthesis via a chemical stabilization of tetrahydrobiopterin. J Biol Chem. 2001;276(1):40–7. 89. Lutsenko EA, Cárcamo JM, Golde DW. Vitamin C prevents DNA mutation induced by oxidative stress. J Biol Chem. 2002;277(19):16895–9. 90. Placzek M, Gaube S, Kerkmann U, Gilbertz K-P, Herzinger T, Haen E, u. a. Ultraviolet B- induced DNA damage in human epidermis is modified by the antioxidants ascorbic acid and D-alpha-tocopherol. J Invest Dermatol. 2005;124(2):304–7. 91. Moison RMW, Beijersbergen van Henegouwen GMJ. Topical antioxidant vitamins C and E prevent UVB-radiation-induced peroxidation of eicosapentaenoic acid in pig skin. Radiat Res. 2002;157(4):402–9. 92. Frei B, England L, Ames BN. Ascorbate is an outstanding antioxidant in human blood plasma. Proc Natl Acad Sci U S A. 1989;86(16):6377–81. 93. Farris PK. Topical vitamin C: a useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg Off Publ Am Soc Dermatol Surg Al. 2005;31(7 Pt 2):814–7. 94. Huh C-H, Seo K-I, Park J-Y, Lim J-G, Eun H-C, Park K-C. A randomized, double-blind, placebo-controlled trial of vitamin C iontophoresis in melasma. Dermatol Basel Switz. 2003;206(4):316–20. 95. Cohn W. Bioavailability of vitamin E. Eur J Clin Nutr. 1997;51 Suppl 1:S80–5. 96. Kelly FJ. Use of antioxidants in the prevention and treatment of disease. J Int Fed Clin Chem IFCC. 1998;10(1):21–3. 97. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347(9004):781–6. 98. Ricciarelli R, Zingg JM, Azzi A. Vitamin E reduces the uptake of oxidized LDL by inhibiting CD36 scavenger receptor expression in cultured aortic smooth muscle cells. Circulation. 2000;102(1):82–7. 99. De Nigris F, Franconi F, Maida I, Palumbo G, Anania V, Napoli C. Modulation by alpha- and gamma-tocopherol and oxidized low-density lipoprotein of apoptotic signaling in human coronary smooth muscle cells. Biochem Pharmacol. 2000;59(11):1477–87. 100. Thiele JJ, Traber MG, Packer L. Depletion of human stratum corneum vitamin E: an early and sensitive in vivo marker of UV induced photo-oxidation. J Invest Dermatol. 1998;110(5):756–61. 76 101. Darr D, Dunston S, Faust H, Pinnell S. Effectiveness of antioxidants (vitamin C and E) with and without sunscreens as topical photoprotectants. Acta Derm Venereol. 1996;76(4):264–8. 102. Lin J-Y, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, u. a. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol. 2003;48(6):866–74. 103. Yuen KS, Halliday GM. alpha-Tocopherol, an inhibitor of epidermal lipid peroxidation, prevents ultraviolet radiation from suppressing the skin immune system. Photochem Photobiol. 1997;65(3):587–92. 104. Bissett DL, Chatterjee R, Hannon DP. Photoprotective effect of topical anti-inflammatory agents against ultraviolet radiation-induced chronic skin damage in the hairless mouse. Photodermatol Photoimmunol Photomed. 1990;7(4):153–8. 105. Burke KE, Clive J, Combs GF Jr, Commisso J, Keen CL, Nakamura RM. Effects of topical and oral vitamin E on pigmentation and skin cancer induced by ultraviolet irradiation in Skh:2 hairless mice. Nutr Cancer. 2000;38(1):87–97. 106. Murray JC, Burch JA, Streilein RD, Iannacchione MA, Hall RP, Pinnell SR. A topical antioxidant solution containing vitamins C and E stabilized by ferulic acid provides protection for human skin against damage caused by ultraviolet irradiation. J Am Acad Dermatol. 2008;59(3):418–25. 107. Black HS. Interaction of ascorbic acid and tocopherol on beta-carotene modulated carcinogenesis. Hemoglobin. 2010;34(3):284–90. 108. Werninghaus K, Meydani M, Bhawan J, Margolis R, Blumberg JB, Gilchrest BA. Evaluation of the photoprotective effect of oral vitamin E supplementation. Arch Dermatol. 1994;130(10):1257–61. 109. McArdle F, Rhodes LE, Parslew RAG, Close GL, Jack CIA, Friedmann PS, u. a. Effects of oral vitamin E and beta-carotene supplementation on ultraviolet radiation-induced oxidative stress in human skin. Am J Clin Nutr. 2004;80(5):1270–5. 110. Sies H, Stahl W. Carotenoids and UV protection. Photochem Photobiol Sci Off J Eur Photochem Assoc Eur Soc Photobiol. 2004;3(8):749–52. 111. Mayne ST. Beta-carotene, carotenoids, and disease prevention in humans. FASEB J Off Publ Fed Am Soc Exp Biol. 1996;10(7):690–701. 112. Aust O, Sies H, Stahl W, Polidori MC. Analysis of lipophilic antioxidants in human serum and tissues: tocopherols and carotenoids. J Chromatogr A. 30. 2001;936(1-2):83–93. 113. Sakurai H, Yasui H, Yamada Y, Nishimura H, Shigemoto M. Detection of reactive oxygen species in the skin of live mice and rats exposed to UVA light: a research review on chemiluminescence and trials for UVA protection. Photochem Photobiol Sci Off J Eur Photochem Assoc Eur Soc Photobiol. 2005;4(9):715–20. 77 114. Stahl W, Sies H. Carotenoids and flavonoids contribute to nutritional protection against skin damage from sunlight. Mol Biotechnol. 2007;37(1):26–30. 115. Köpcke W, Krutmann J. Protection from sunburn with beta-Carotene--a meta-analysis. Photochem Photobiol. 2008;84(2):284–8. 116. Camera E, Mastrofrancesco A, Fabbri C, Daubrawa F, Picardo M, Sies H, u. a. Astaxanthin, canthaxanthin and beta-carotene differently affect UVA-induced oxidative damage and expression of oxidative stress-responsive enzymes. Exp Dermatol. 2009;18(3):222–31. 117. Young AJ, Lowe GM. Antioxidant and prooxidant properties of carotenoids. Arch Biochem Biophys. 2001;385(1):20–7. 118. El-Agamey A, Lowe GM, McGarvey DJ, Mortensen A, Phillip DM, Truscott TG, u. a. Carotenoid radical chemistry and antioxidant/pro-oxidant properties. Arch Biochem Biophys. 2004;430(1):37–48. 119. Biesalski HK, Obermueller-Jevic UC. UV light, beta-carotene and human skin--beneficial and potentially harmful effects. Arch Biochem Biophys. 2001;389(1):1–6. 120. Blagojevic D, Schenk T, Haas O, Zierhofer B, Konnaris C, Trautinger F. Acquired erythropoietic protoporphyria. Ann Hematol. 2010;89(7):743–4. 121. Kanofsky JR, Sima PD. Activity of a cationic carotenoid derivative in a mouse model of protoporphyria. J Photochem Photobiol B. 2007;87(2):124–9. 122. Mathews-Roth MM. Carotenoids in erythropoietic protoporphyria and other photosensitivity diseases. Ann N Y Acad Sci. 1993;691:127–38. 123. Holme SA, Anstey AV, Finlay AY, Elder GH, Badminton MN. Erythropoietic protoporphyria in the U.K.: clinical features and effect on quality of life. Br J Dermatol. 2006;155(3):574–81. 124. Kollias N, Sayre RM, Zeise L, Chedekel MR. Photoprotection by melanin. J Photochem Photobiol B. 1991;9(2):135–60. 125. Prota G. The chemistry of melanins and melanogenesis. Fortschritte Chem Org Naturstoffe Prog Chem Org Nat Prod Prog Dans Chim Subst Org Nat. 1995;64:93–148. 126. Ito S. The IFPCS presidential lecture: a chemist’s view of melanogenesis. Pigment Cell Res Spons Eur Soc Pigment Cell Res Int Pigment Cell Soc. 2003;16(3):230–6. 127. Ito S. Reexamination of the structure of eumelanin. Biochim Biophys Acta. 1986;883(1):155–61. 128. Nofsinger JB, Forest SE, Eibest LM, Gold KA, Simon JD. Probing the building blocks of eumelanins using scanning electron microscopy. Pigment Cell Res Spons Eur Soc Pigment Cell Res Int Pigment Cell Soc. 2000;13(3):179–84. 78 129. Meredith P, Sarna T. The physical and chemical properties of eumelanin. Pigment Cell Res Spons Eur Soc Pigment Cell Res Int Pigment Cell Soc. 2006;19(6):572–94. 130. Swan GA. Structure, chemistry, and biosynthesis of the melanins. Fortschritte Chem Org Naturstoffe Prog Chem Org Nat Prod Prog Dans Chim Subst Org Nat. 1974;31(0):521–82. 131. Nofsinger JB, Liu Y, Simon JD. Aggregation of eumelanin mitigates photogeneration of reactive oxygen species. Free Radic Biol Med. 2002;32(8):720–30. 132. D’ Ischia M, Napolitano A, Pezzella A, Meredith P, Sarna T. Chemical and structural diversity in eumelanins: unexplored bio-optoelectronic materials. Angew Chem Int Ed Engl. 2009;48(22):3914–21. 133. Rees JL. Genetics of hair and skin color. Annu Rev Genet. 2003;37:67–90. 134. Valverde P, Healy E, Jackson I, Rees JL, Thody AJ. Variants of the melanocyte- stimulating hormone receptor gene are associated with red hair and fair skin in humans. Nat Genet. 1995;11(3):328–30. 135. Rouzaud F, Kadekaro AL, Abdel-Malek ZA, Hearing VJ. MC1R and the response of melanocytes to ultraviolet radiation. Mutat Res. 2005;571(1-2):133–52. 136. Gantz I, Fong TM. The melanocortin system. Am J Physiol Endocrinol Metab. 2003;284(3):E468–74. 137. Song X, Mosby N, Yang J, Xu A, Abdel-Malek Z, Kadekaro AL. alpha-MSH activates immediate defense responses to UV-induced oxidative stress in human melanocytes. Pigment Cell Melanoma Res. 2009;22(6):809–18. 138. Cui R, Widlund HR, Feige E, Lin JY, Wilensky DL, Igras VE, u. a. Central role of p53 in the suntan response and pathologic hyperpigmentation. Cell. 2007;128(5):853–64. 139. Gilchrest BA, Park HY, Eller MS, Yaar M. Mechanisms of ultraviolet light-induced pigmentation. Photochem Photobiol. 1996;63(1):1–10. 140. Barsh G, Attardi LD. A healthy tan? N Engl J Med. 2007;356(21):2208–10. 141. April CS, Barsh GS. Distinct pigmentary and melanocortin 1 receptor-dependent components of cutaneous defense against ultraviolet radiation. PLoS Genet. 2007;3(1):e9. 142. Robinson S, Dixon S, August S, Diffey B, Wakamatsu K, Ito S, u. a. Protection against UVR involves MC1R-mediated non-pigmentary and pigmentary mechanisms in vivo. J Invest Dermatol. 2010;130(7):1904–13. 143. Abdel-Malek ZA, Ruwe A, Kavanagh-Starner R, Kadekaro AL, Swope V, Haskell- Luevano C, u. a. alpha-MSH tripeptide analogs activate the melanocortin 1 receptor and reduce UV-induced DNA damage in human melanocytes. Pigment Cell Melanoma Res. 2009;22(5):635–44. 79 144. Dong L, Wen J, Pier E, Zhang X, Zhang B, Dong F, u. a. Melanocyte-stimulating hormone directly enhances UV-Induced DNA repair in keratinocytes by a xeroderma pigmentosum group A-dependent mechanism. Cancer Res. 2010;70(9):3547–56. 145. Kokot A, Metze D, Mouchet N, Galibert M-D, Schiller M, Luger TA, u. a. Alpha- melanocyte-stimulating hormone counteracts the suppressive effect of UVB on Nrf2 and Nrf-dependent gene expression in human skin. Endocrinology. 2009;150(7):3197–206. 146. Sawyer TK, Sanfilippo PJ, Hruby VJ, Engel MH, Heward CB, Burnett JB, u. a. 4- Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980;77(10):5754–8. 147. Fitzgerald LM, Fryer JL, Dwyer T, Humphrey SM. Effect of Melanotan, [Nle(4), D- Phe(7)]-alpha-MSH, on melanin synthesis in humans with MC1R variant alleles. Peptides. 2006;27(2):388–94. 148. Schallreuter KU, Kothari S, Chavan B, Spencer JD. Regulation of melanogenesis-- controversies and new concepts. Exp Dermatol. 2008;17(5):395–404. 149. Rosenbruch M. Toxicity studies of the incubated chicken egg. With special reference to the extra-embryonal vascular systems. Dermatosen Beruf Umw Occup Environ. 1990;38(1):5– 11. 150. Bafteh PR, Siegesmund M, Hanneken S, Neumann NJ. Protective effects of β-carotene and melanin against protoporphyrine IX-induced phototoxicity in the photo hen’s egg test. Photodermatol Photoimmunol Photomed. 2012;28(1):12–6. 150a. Bafteh PR, Siegesmund M, Kuerten V, Neumann NJ. Phototoxicity of narrowband ultraviolet (UV) B (311 nm) compared with broadband UVB in the photo hen’s egg test. Br J Dermatol. 2015;172(2):462-6. 151. Böhm F, Edge R, Foley S, Lange L, Truscott TG. Antioxidant inhibition of porphyrin- induced cellular phototoxicity. J Photochem Photobiol B. 2001;65(2-3):177–83. 152. Emri S, Kilickap S, Kadilar C, Halil MG, Akay H, Besler T. Serum levels of alpha- tocopherol, vitamin C, beta-carotene, and retinol in malignant pleural mesothelioma. Asian Pac J Cancer Prev APJCP. 2012;13(7):3025–9. 153. Breidenassel C, Valtueña J, González-Gross M, Benser J, Spinneker A, Moreno LA, u. a. Antioxidant Vitamin Status (A, E, C, and Beta-Carotene) in European Adolescents - The HELENA Study. Int J Vitam Nutr Res. 2011;81(4):245–55. 154. Dauchet L, Péneau S, Bertrais S, Vergnaud AC, Estaquio C, Kesse-Guyot E, u. a. Relationships between different types of fruit and vegetable consumption and serum concentrations of antioxidant vitamins. Br J Nutr. 2008;100(03):633–41. 80 155. Fischer-Nielsen A, Loft S, Jensen KG. Effect of ascorbate and 5-aminosalicylic acid on light-induced 8-hydroxydeoxyguanosine formation in V79 Chinese hamster cells. Carcinogenesis. 1993;14(11):2431–3. 156. Stewart MS, Cameron GS, Pence BC. Antioxidant nutrients protect against UVB-induced oxidative damage to DNA of mouse keratinocytes in culture. J Invest Dermatol. 1996;106(5):1086–9. 157. Darr D, Combs S, Dunston S, Manning T, Pinnell S. Topical vitamin C protects porcine skin from ultraviolet radiation-induced damage. Br J Dermatol. 1992;127(3):247–53. 158. Yoshikawa Y, Hizume K, Oda Y, Takeyasu K, Araki S, Yoshikawa K. Protective effect of vitamin C against double-strand breaks in reconstituted chromatin visualized by single- molecule observation. Biophys J. 2006;90(3):993–9. 159. Halliwell B. Vitamin C: antioxidant or pro-oxidant in vivo? Free Radic Res. 1996;25(5):439–54. 160. Jayasinghe C, Gotoh N, Wada S. Pro-oxidant/antioxidant behaviours of ascorbic acid, tocopherol, and plant extracts in n-3 highly unsaturated fatty acid rich oil-in-water emulsions. Food Chem. 2013;141(3):3077–84. 161. Paolini M, Pozzetti L, Pedulli GF, Marchesi E, Cantelli-Forti G. The nature of prooxidant activity of vitamin C. Life Sci. 1999;64(23):PL 273–8. 162. Eberlein-König B, Placzek M, Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E). J Am Acad Dermatol. 1998;38(1):45–8. 163. Ishikawa Y, Hashizume K, Kishimoto S, Tezuka Y, Nishigori H, Yamamoto N, u. a. Effect of vitamin C depletion on UVR-B induced cataract in SMP30/GNL knockout mice. Exp Eye Res. 2012;94(1):85–9. 164. Sinclair PR, Gorman N, Walton HS, Bement WJ, Jacobs JM, Sinclair JF. Ascorbic acid inhibition of cytochrome P450-catalyzed uroporphyrin accumulation. Arch Biochem Biophys. 1993;304(2):464–70. 165. Sinclair PR, Gorman N, Sinclair JF, Walton HS, Bement WJ, Lambrecht RW. Ascorbic acid inhibits chemically induced uroporphyria in ascorbate-requiring rats. Hepatol Baltim Md. 1995;22(2):565–72. 166. Trevithick JR, Xiong H, Lee S, Shum DT, Sanford SE, Karlik SJ, Norley C, u. a. Topical tocopherol acetate reduces post-UVB, sunburn-associated erythema, edema, and skin sensitivity in hairless mice. Arch Biochem Biophys. 1992;296(2):575–82. 167. Kondo S, Mamada A, Yamaguchi J, Fukuro S. Protective effect of dl-alpha-tocopherol on the cytotoxicity of ultraviolet B against human skin fibroblasts in vitro. Photodermatol Photoimmunol Photomed. 1990;7(4):173–7. 81 168. Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. Topical application of alpha- tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin. Br J Dermatol. 1998;138(2):207–15. 169. Jurkiewicz BA, Bissett DL, Buettner GR. Effect of topically applied tocopherol on ultraviolet radiation-mediated free radical damage in skin. J Invest Dermatol. 1995;104(4):484–8. 170. Steenvoorden DP, Beijersbergen van Henegouwen G. Protection against UV-induced systemic immunosuppression in mice by a single topical application of the antioxidant vitamins C and E. Int J Radiat Biol. 1999;75(6):747–55. 171. Ingold KU, Webb AC, Witter D, Burton GW, Metcalfe TA, Muller DP. Vitamin E remains the major lipid-soluble, chain-breaking antioxidant in human plasma even in individuals suffering severe vitamin E deficiency. Arch Biochem Biophys. 1987;259(1):224–5. 172. Traber MG. Vitamin E regulation. Curr Opin Gastroenterol. 2005;21(2):223–7. 173. Murr C, Winklhofer-Roob BM, Schroecksnadel K, Maritschnegg M, Mangge H, Böhm BO, u. a. Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease. Atherosclerosis. 2009;202(2):543–9. 174. Sies H, Stahl W. Nutritional protection against skin damage from sunlight. Annu Rev Nutr. 2004;24:173–200. 175. Stratton SP, Liebler DC. Determination of singlet oxygen-specific versus radical-mediated lipid peroxidation in photosensitized oxidation of lipid bilayers: effect of beta-carotene and alpha-tocopherol. Biochemistry (Mosc). 1997;36(42):12911–20. 176. Mathews-Roth MM, Pathak MA, Parrish J, Fitzpatrick TB, Kass EH, Toda K, u. a. A clinical trial of the effects of oral beta-carotene on the responses of human skin to solar radiation. J Invest Dermatol. 1972;59(4):349–53. 177. Giles A Jr, Wamer W, Kornhauser A. In vivo protective effect of beta-carotene against psoralen phototoxicity. Photochem Photobiol. 1985;41(6):661–6. 178. Mathews-Roth MM. Treatment of erythropoietic protoporphyria with beta-carotene. Photodermatol. 1984;1(6):318–21. 179. Corbett MF, Herxheimer A, Magnus IA, Ramsay CA, Kobza-Black A. The long term treatment with beta-carotene in erythropoietic protoporphyria: a controlled trial. Br J Dermatol. 1977;97(6):655–62. 180. Wahlin S, Floderus Y, Stål P, Harper P. Erythropoietic protoporphyria in Sweden: demographic, clinical, biochemical and genetic characteristics. J Intern Med. 2011;269(3):278–88. 82 181. Shono S, Imura M, Ota M, Ono S, Toda K. The relationship of skin color, UVB-induced erythema, and melanogenesis. J Invest Dermatol. 1985;84(4):265–7. 182. Olson RL, Gaylor J, Everett MA. Skin color, melanin, and erythema. Arch Dermatol. 1973;108(4):541–4. 183. Herrling T, Jung K, Fuchs J. The role of melanin as protector against free radicals in skin and its role as free radical indicator in hair. Spectrochim Acta A Mol Biomol Spectrosc. 2008;69(5):1429–35. 184. Korytowski W, Pilas B, Sarna T, Kalyanaraman B. Photoinduced Generation of Hydrogen Peroxide and Hydroxyl Radicals in Melanins. Photochem Photobiol. 1987;45(2):185–90. 185. Minder EI. Afamelanotide, an agonistic analog of α-melanocyte-stimulating hormone, in dermal phototoxicity of erythropoietic protoporphyria. Expert Opin Investig Drugs. 2010;19(12):1591–602. 186. Pecourt JM, Peon J, Kohler B. DNA excited-state dynamics: ultrafast internal conversion and vibrational cooling in a series of nucleosides. J Am Chem Soc. 2001;123(42):10370–8. 187. Meng S, Kaxiras E. Mechanisms for ultrafast nonradiative relaxation in electronically excited eumelanin constituents. Biophys J. 2008;95(9):4396–402. 188. McCamant DW, Kukura P, Mathies RA. Femtosecond Time-Resolved Stimulated Raman Spectroscopy: Application to the Ultrafast Internal Conversion in beta-Carotene. J Phys Chem A. 2003;107(40):8208–14. 189. Tadokoro T, Kobayashi N, Zmudzka BZ, Ito S, Wakamatsu K, Yamaguchi Y, u. a. UV- induced DNA damage and melanin content in human skin differing in racial/ethnic origin. FASEB J Off Publ Fed Am Soc Exp Biol. 2003;17(9):1177–9. 190. Kawamura T, Fitzpatrick TB, Seiji M. The photobiology of melanin pigmentation in human skin. Biology of Normal and Abnormal Melanocytes. Baltimore: University Park Press; S. 149–70. 191. Szabó G, Gerald AB, Pathak MA, Fitzpatrick TB. Racial differences in the fate of melanosomes in human epidermis. Nature. 1969;222(5198):1081–2. 192. Kobayashi N, Nakagawa A, Muramatsu T, Yamashina Y, Shirai T, Hashimoto MW, u. a. Supranuclear melanin caps reduce ultraviolet induced DNA photoproducts in human epidermis. J Invest Dermatol. 1998;110(5):806–10. 193. Hearing VJ. The melanosome: the perfect model for cellular responses to the environment. Pigment Cell Res Spons Eur Soc Pigment Cell Res Int Pigment Cell Soc. 2000;13 Suppl 8:23–34. 194. Tada A, Suzuki I, Im S, Davis MB, Cornelius J, Babcock G, u. a. Endothelin-1 is a paracrine growth factor that modulates melanogenesis of human melanocytes and 83 participates in their responses to ultraviolet radiation. Cell Growth Differ Mol Biol J Am Assoc Cancer Res. 1998;9(7):575–84. 195. Levine N, Sheftel SN, Eytan T, Dorr RT, Hadley ME, Weinrach JC, u. a. Induction of skin tanning by subcutaneous administration of a potent synthetic melanotropin. JAMA J Am Med Assoc. 1991;266(19):2730–6. 196. Dorr RT, Dvorakova K, Brooks C, Lines R, Levine N, Schram K, u. a. Increased eumelanin expression and tanning is induced by a superpotent melanotropin [Nle4-D- Phe7]-alpha-MSH in humans. Photochem Photobiol. 2000;72(4):526–32. 197. Barnetson RS, Ooi TKT, Zhuang L, Halliday GM, Reid CM, Walker PC, u. a. [Nle4-D- Phe7]-alpha-melanocyte-stimulating hormone significantly increased pigmentation and decreased UV damage in fair-skinned Caucasian volunteers. J Invest Dermatol. 2006;126(8):1869–78. 198. Loser K, Brzoska T, Oji V, Auriemma M, Voskort M, Kupas V, u. a. The neuropeptide alpha-melanocyte-stimulating hormone is critically involved in the development of cytotoxic CD8+ T cells in mice and humans. PloS One. 2010;5(2):e8958. 199. Jong CT, Finlay AY, Pearse AD, Kerr AC, Ferguson J, Benton EC, u. a. The quality of life of 790 patients with photodermatoses. Br J Dermatol. 2008;159(1):192–7. 200. Pawliuk R, Bachelot T, Wise RJ, Mathews-Roth MM, Leboulch P. Long-term cure of the photosensitivity of murine erythropoietic protoporphyria by preselective gene therapy. Nat Med. 1999;5(7):768–73. 201. Richard E, Mendez M, Mazurier F, Morel C, Costet P, Xia P, u. a. Gene therapy of a mouse model of protoporphyria with a self-inactivating erythroid-specific lentiviral vector without preselection. Mol Ther J Am Soc Gene Ther. 2001;4(4):331–8. 202. Poh-Fitzpatrick MB, Wang X, Anderson KE, Bloomer JR, Bolwell B, Lichtin AE. Erythropoietic protoporphyria: altered phenotype after bone marrow transplantation for myelogenous leukemia in a patient heteroallelic for ferrochelatase gene mutations. J Am Acad Dermatol. 2002;46(6):861–6. 203. Wahlin S, Aschan J, Björnstedt M, Broomé U, Harper P. Curative bone marrow transplantation in erythropoietic protoporphyria after reversal of severe cholestasis. J Hepatol. 2007;46(1):174–9. 204. Fabrikant J, Touloei K, Brown SM. A review and update on melanocyte stimulating hormone therapy: afamelanotide. J Drugs Dermatol JDD. 2013;12(7):775–9. 205. Holst C, Boix A, Baeten V, Vancutsem J, Berben G. Determination of processed animal proteins in feed: The performance charasteristics of classical microscopy and immunoassay methods. Food Addit Contam. 2006;23(3):252-64. | |||||||
| Rechtliche Vermerke: | keine | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Bezug: | 2009-2018
Porphyria Specalist Center, Klinik für Dermatologie, Universitätsklinikum Düsseldorf | |||||||
| Fachbereich / Einrichtung: | Medizinische Fakultät | |||||||
| Dokument erstellt am: | 01.02.2018 | |||||||
| Dateien geändert am: | 01.02.2018 | |||||||
| Promotionsantrag am: | 23.03.2017 | |||||||
| Datum der Promotion: | 30.01.2018 |
