Journal of Literature Pharmacy Sciences

Hiperisin: Fotodinamik Terapi, Hiperisizm ve Fototoksisite
Hypericin: Photodynamic Therapy, Hypericism, and Phototoxicity
Ezgi ERSOYa, Esra EROĞLU ÖZKANa, Afife MATa
aİstanbul Üniversitesi Eczacılık Fakültesi, Farmakognozi ABD, İstanbul, TÜRKİYE
J Lit Pharm Sci. 2021;10(3):296-307
doi: 10.5336/pharmsci.2021-83782
Article Language: TR
Full Text
ÖZET
Kimyasal bileşimlerinde bulunan naftodiantron türevi bileşikler nedeniyle birçok Hypericum türünün fototoksik aktivite gösterdiği bilinmektedir. Bu türler arasında en yaygın olarak kullanılan ve üzerinde en fazla araştırma yapılmış olan Hypericum perforatum (sarı kantaron) türü de fototoksik bir bitkidir. Bu bitkilerin koyu renkli salgı bezlerinde sentezlenen ve bir naftodiantron türevi olan hiperisin, fototoksisiteden sorumlu majör bileşiktir. Hiperisin içeren bitkilerin fototoksik etkileri ilk kez, Hypericum türlerinden fazlaca tüketen açık renk derili veya postlu, koyun gibi hayvanların güneş altında otlarken derilerinde meydana gelen ve bazen ölümle sonuçlanan ciddi reaksiyonlar oluşmasıyla keşfedilmiştir. Hayvanlarda görülen bu hastalığa 'Hiperisizm' adı verilmiştir. Bu durum, dâhilen antidepresan haricen de yara iyileştirici etkisi nedeniyle tüm dünyada çok yaygın olarak kullanılan H. perforatum bitkisinin insanlardaki fototoksisite potansiyeli hakkında bilgi edinmeyi zorunlu hâle getirmiştir. Diğer yandan güçlü fotodinamik aktivitesi sayesinde farmasötik açıdan oldukça önemli bir molekül olan hiperisin; özellikle kanser ve AIDS hastalıklarının fotodinamik terapiyle tedavisinde umut vaat eden bir bileşik olarak değerlendirilmektedir. Ayrıca fotodinamik terapide, fotosensibilizan ajan olarak hiperisin kullanımının diğer fototoksik maddelere kıyasla ciddi avantajlar sağladığı görülmüştür. Bu derleme, Hypericum türlerinin fototoksisitesi, hiperisinin fotodinamik aktivitesi, fotodinamik terapide kullanılışı ve diğer farmakolojik özellikleriyle ilgili detaylı bilgi vermek üzere hazırlanmıştır.

Anahtar Kelimeler: Hypericum; sarı kantaron; hiperisin; fototoksisite; fotodinamik terapi
ABSTRACT
Most of the Hypericum species, including the most wellknown, commonly used, and extensively investigated Hypericum perforatum, (common St. John's Wort) are known to be phototoxic plants, due to the naphthodianthrone derivatives present in their chemical compositions. Hypericin, a naphthodianthrone, that is synthesized and stored in their dark glands, is the major compound responsible for their phototoxicity. The phototoxicity of the hypericin containing plants was first discovered in certain light-skinned animals, such as sheep that would have severe skin reactions, and even die from ingesting large quantities of Hypericum species while grazing, and of exposure to sun after. This disease in animals was named as 'Hypericism'. Being widely used mainly for its antidepressant effect internally and its wound-healing properties externally, it has become crucial to gain more knowledge about the phototoxic potential of H. perforatum in humans. Furthermore, having strong photodynamic activities, hypericin was found to be a molecule of high pharmaceutical importance, and considered as a promising agent for cancer and AIDS therapies. More importantly, in the search for new photosensitizers for photodynamic therapy, hypericin was found to have many serious advantages in comparison to other phototoxic agents. This review was designed to give detailed information about the phototoxicity of Hypericum species, the photodynamic activity, and pharmacological properties of hypericin including its use in photodynamic therapy.

Keywords: Hypericum; St. John's Wort; hypericin; phototoxicity; photodynamic therapy
REFERENCES:
  1. Fu PP, Xia Q, Zhao Y, Wang S, Yu H, Chiang HM. Phototoxicity of herbal plants and herbal products. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2013;31(3):213-55. [Crossref] [PubMed] 
  2. Baytop T. Türkiye'de Bitkiler ile Tedavi Geç mişte ve Bugün. 2. Baskı. İstanbul: Nobel Tıp Kitabevi; 1999. [Link] 
  3. Giese AC. Hypericism. In: Smith KC, ed. Photochemical and Photobiological Reviews. 1st ed. Boston, MA: Springer; 1980. p.229-55. [Crossref] 
  4. Ersoy E, Eroğlu Özkan E, Mat A. Yeni çalışmalar ışığında Hypericum türlerinin farmakolojik aktiviteleri [Pharmacological activities of Hypericum species in light of new studies]. SABİAD. 2019;2(2):71-9. [Crossref] 
  5. Napoli E, Siracusa L, Ruberto G, Carrubba A, Lazzara S, Speciale A, et al. Phytochemical profiles, phototoxic and antioxidant properties of eleven Hypericum species - a comparative study. Phytochemistry. 2018;152:162-73. [Crossref] [PubMed] 
  6. Stupáková V, Varinská L, Mirossay A, Sarisský M, Mojzis J, Dankovcík R, et al. Photodynamic effect of hypericin in primary cultures of human umbilical endothelial cells and glioma cell lines. Phytother Res. 2009;23(6):827-32. [Crossref] [PubMed] 
  7. Kitanov GM. Hypericin and pseudohypericin in some Hypericum species. Biochem Syst Ecol. 2001;29(2):171-8. [Crossref] [PubMed] 
  8. Guedes RC, Eriksson LA. Theoretical study of hypericin. J Photochem. A: Chemistry. 2005; 172(3):293-9. [Crossref] 
  9. Ersoy E, Özkan EE. Geçmişten günümüze Hypericum perforatum (Sarı Kantaron) ve depresyon tedavisi-neler biliyoruz? [Hypericum perforatum (St John's Wort) for depression treatment from past to present-what do we know?]. J Lit Pharm Sci. 2020. [Link] 
  10. Hudson JB, Lopez-Bazzocchi I, Towers GH. Antiviral activities of hypericin. Antiviral Res. 1991;15(2):101-12. [Crossref] [PubMed] 
  11. Müller WE. St. John's Wort and Its Active Principles in Depression and Anxiety. 1st ed. Basel-Switzerland: Springer Science & Business Media; 2005. [Crossref] 
  12. Pfaffel-Schubart G, Rück A, Scalfi-Happ C. Modulation of cellular Ca2+-signaling during hypericin-induced photodynamic therapy (PDT). Med Laser Appl. 2006;21(1):61-6. [Crossref] 
  13. ESCOP Monographs. The Scientific Foundation for Herbal Medicinal Products. 2nd ed. New York: Thieme; 2003. [Link] 
  14. Ernst E. Hypericum: The Genus Hypericum. 1st ed. ABD: CRC Press; 2003. [Crossref] 
  15. Contis ET, Ho CT, Mussinan CJ, Parliment TH, Shahidi F, Spanier AM, eds. Food Flavors: Formation, Analysis and Packaging Influences. 1st ed. USA: Elsevier; 1998. [Link] 
  16. Pace N, Mackinney G. Hypericin, the photodynamic pigment from St. John's wort. J Am Chem Soc. 1941;63(10):2570-4. [Crossref] 
  17. Duráan N, Song PS. Hypericin and its photodynamic action. Photochem. 1986;43(6):677-80. [Crossref]  [PubMed] 
  18. Karioti A, Bilia AR. Hypericins as potential leads for new therapeutics. Int J Mol Sci. 2010;11(2):562-94. [PubMed] [PMC] 
  19. Huang LF, Wang ZH, Chen SL. Hypericin: chemical synthesis and biosynthesis. Chin J Nat Med. 2014;12(2):81-8. [Crossref] [PubMed] 
  20. Hölzl J, Petersen M. Chemical constituents of Hypericum ssp. Hypericum: the genus Hypericum, 78, CRC Press, USA; 2003.
  21. Jendželovská Z, Jendželovský R, Kuchárová B, Fedoročko P. Hypericin in the light and in the dark: two sides of the same coin. Front Plant Sci. 2016;7:560. [Crossref] [PubMed] [PMC] 
  22. Ersoy E. Uludağ'da yetişen üç Hypericum türünün kimyasal bileşikleri ve biyolojik aktiviteleri üzerinde araştırmalar [Doktora tezi]. İstanbul: İstanbul Üniversitesi Sağlık Bilimleri Enstitüsü; 2019. [Link] 
  23. Carpenter S, Fehr MJ, Kraus GA, Petrich JW. Chemiluminescent activation of the antiviral activity of hypericin: a molecular flashlight. Proc Natl Acad Sci U S A. 1994;91(25): 12273-7. [Crossref] [PubMed] [PMC] 
  24. Feruszová J, Imreová P, Bodnárová K, ?evčovičová A, Kyzek S, Chalupa I, et al. Photoactivated hypericin is not genotoxic. Gen Physiol Biophys. 2016;35(2):223-30. [Crossref] [PubMed] 
  25. Utsumi T, Okuma M, Kanno T, Takehara TY, Yoshioka T, Fujita Y, et al. Effect of the antiretroviral agent hypericin on rat liver mitochondria, Biochem Pharmacol. 1995;50(5):655-62. [Crossref] 
  26. Hadjur C, Richard MJ, Parat MO, Jardon P, Favier A. Photodynamic effects of hypericin on lipid peroxidation and antioxidant status in melanoma cells. Photochem Photobiol. 1996;64(2):375-81. [Crossref] [PubMed] 
  27. Chaloupka R, Obsil T, Plásek J, Sureau F. The effect of hypericin and hypocrellin-a on lipid membranes and membrane potential of 3T3 fibroblasts. Biochim Biophys Acta. 1999;1418(1):39-47. [Crossref] [PubMed] 
  28. Singh AP. Hypericin- a napthodianthrone from Hypericum perforatum. Ethnobotanical Leaflets. 2005;2003(1):11. [Link] 
  29. Popovic A, Wiggins T, Davids LM. Differential susceptibility of primary cultured human skin cells to hypericin PDT in an in vitro model. J Photochem Photobiol B. 2015;149:249-56. [Crossref] [PubMed] 
  30. Vandenbogaerde AL, Kamuhabwa A, Delaey E, Himpens BE, Merlevede WJ, de Witte PA. Photocytotoxic effect of pseudohypericin versus hypericin. J Photochem: Biology, 1998;45(2-3): 87-94. [Crossref] 
  31. Kaushal R, Goklany S. Cancer Therapeutics and Imaging: Molecular and Cellular Engineering and Nanobiomedicine. Vol. 11. 1st ed. USA: World Scientific; 2017. [Link] 
  32. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. J Natl Cancer Inst. 1998;90(12):889-905. [Crossref] [PubMed] [PMC] 
  33. Garg AD, Krysko DV, Vandenabeele P, Agostinis P. Hypericin-based photodynamic therapy induces surface exposure of damage-associated molecular patterns like HSP70 and calreticulin. Cancer Immunol Immunother. 2012; 61(2):215-21. Erratum in: Cancer Immunol Immunother. 2018;8. [Crossref]  [PubMed] 
  34. Koren H, Schenk GM, Iindra RH, Alth G, Ebermann R, Kubin A, et al. Hypericin in phototherapy. J Photochem B: Biology. 1996; 36(2):113-9. [Crossref] 
  35. Du HY, Bay BH, Olivo M. Biodistribution and photodynamic therapy with hypericin in a human NPC murine tumor model. Int J Oncol. 2003;22(5):1019-24. [Crossref] [PubMed] 
  36. Kamuhabwa A, Agostinis P, Ahmed B, Landuyt W, van Cleynenbreugel B, van Poppel H, et al. Hypericin as a potential phototherapeutic agent in superficial transitional cell carcinoma of the bladder. Photochem Photobiol Sci. 2004;3(8):772-80. [Crossref] [PubMed] 
  37. Seitz G, Krause R, Fuchs J, Heitmann H, Armeanu S, Ruck P, et al. In vitro photodynamic therapy in pediatric epithelial liver tumors promoted by hypericin. Oncol Rep. 2008;20(5):1277-82. [PubMed] 
  38. Liu L, Song Y, Ma L, Zang L, Tao L, Zhang Z, et al. Growth inhibition effect of HMME-mediated PDT on hepatocellular carcinoma HepG2 cells. Lasers Med Sci. 2014;29(5):1715-22. [Crossref] [PubMed] 
  39. Seitz G, Fuchs J, Schaefer JF, Warmann SW. Molecular imaging and photodynamic therapy in hepatoblastoma. Front Biosci (Elite Ed). 2012;4:487-92. [Crossref] [PubMed] 
  40. Kim H, Kim SW, Seok KH, Hwang CW, Ahn JC, Jin JO, Kang HW. Hypericin-assisted photodynamic therapy against anaplastic thyroid cancer. Photodiagnosis Photodyn Ther. 2018;24:15-21. Epub 2018 Aug 15. [Crossref] [PubMed] 
  41. Damke GMZF, Damke E, de Souza Bonfim-Mendonça P, Ratti BA, de Freitas Meirelles LE, da Silva VRS, Gonçalves RS, César GB, de Oliveira Silva S, Caetano W, Hioka N, Souza RP, Consolaro MEL. Selective photodynamic effects on cervical cancer cells provided by P123 Pluronic®-based nanoparticles modulating hypericin delivery. Life Sci. 2020;255:117858. Epub 2020 Jun 1. [Crossref] [PubMed] 
  42. Höpfner M, Maaser K, Theiss A, Lenz M, Sutter AP, Kashtan H, et al. Hypericin activated by an incoherent light source has photodynamic effects on esophageal cancer cells. Int J Colorectal Dis. 2003;18(3):239-47. [Crossref]  [PubMed] 
  43. Wang X, Zhang J, Liu J, Yang R. Photocytotoxic effect of hypericin extract from Hypericum perforatum L. on MDA231 human mammary carcinoma cell lines in vitro. The Chinese Journal of Modern Applied Pharmacy. 2008;1:1-4. [Link] 
  44. Wessels JT, Busse AC, Rave-Fränk M, Zänker S, Hermann R, Grabbe E, et al. Photosensitizing and radiosensitizing effects of hypericin on human renal carcinoma cells in vitro. Photochem Photobiol. 2008;84(1):228-35. [PubMed] 
  45. Sacková V, Fedorocko P, Szilárdiová B, Mikes J, Kleban J. Hypericin-induced photocytotoxicity is connected with G2/M arrest in HT-29 and S-phase arrest in U937 cells. Photochem Photobiol. 2006;82(5):1285-91. [Crossref]  [PubMed] 
  46. Seitz G, Warmann SW, Armeanu S, Heitmann H, Ruck P, Hoffman RM, et al. In vitro photodynamic therapy of childhood rhabdomyosarcoma. Int J Oncol. 2007;30(3):615-20. [Crossref] [PubMed] 
  47. Theodossiou TA, Hothersall JS, De Witte PA, Pantos A, Agostinis P. The multifaceted photocytotoxic profile of hypericin. Mol Pharm. 2009;6(6):1775-89. [Crossref] [PubMed] 
  48. Skalkos D, Gioti E, Stalikas CD, Meyer H, Papazoglou TG, Filippidis G. Photophysical properties of Hypericum perforatum L. extracts- -novel photosensitizers for PDT. J Photochem Photobiol B. 2006;82(2):146-51. [Crossref] [PubMed] 
  49. Zhang Q, Li ZH, Li YY, Shi SJ, Zhou SW, Fu YY, et al. Hypericin-photodynamic therapy induces human umbilical vein endothelial cell apoptosis. Sci Rep. 2015;5:18398. [Crossref] [PubMed] [PMC] 
  50. Sams WM Jr, Winkelmann RK. The effect of ultraviolet light on isolated cutaneous blood vessels. J Invest Dermatol. 1969;53(1):79-83. [Crossref] [PubMed] 
  51. Bloomfield HH, Nordfors M, McWilliams P. Hypericum (St. John's Wort) and Depression. Los Angeles: Prelude Press; 1996. [Link] 
  52. Bove GM. Acute neuropathy after exposure to sun in a patient treated with St John's Wort. Lancet. 1998;352(9134):1121-2. [Crossref]  [PubMed] 
  53. Golsch S, Vocks E, Rakoski J, Brockow K, Ring J. Reversible Erhöhung der Photosensitivität im UV-B-Bereich durch Johanniskrautextrakt-Präparate. Der Hautarzt. 1997;48(4): 249-52. [Crossref]  [PubMed] 
  54. Gulick RM, McAuliffe V, Holden-Wiltse J, Crumpacker C, Liebes L, Stein DS, et al. Phase I studies of hypericin, the active compound in St. John's Wort, as an antiretroviral agent in HIV-infected adults. AIDS Clinical Trials Group Protocols 150 and 258. Ann Intern Med. 1999;130(6):510-4. [PubMed] 
  55. Brockmöller J, Reum T, Bauer S, Kerb R, Hübner WD, Roots I. Hypericin and pseudohypericin: pharmacokinetics and effects on pho tosensitivity in humans. Pharmacopsychiatry. 1997;30 Suppl 2:94-101. [Crossref] [PubMed] 
  56. Holme SA, Roberts DL. Erythroderma associated with St John's wort. Br J Dermatol. 2000;143(5):1127-8. [Crossref] [PubMed] 
  57. Wielgus AR, Chignell CF, Miller DS, Van Houten B, Meyer J, Hu DN, et al. Phototoxicity in human retinal pigment epithelial cells promoted by hypericin, a component of St. John's wort. Photochem Photobiol. 2007; 83(3):706-13. [Crossref] [PubMed] [PMC] 
  58. Schempp CM, Winghofer B, Müller K, Schulte-Mönting J, Mannel M, Schöpf E, et al. Effect of oral administration ofHypericum perforatum extract (St. John's Wort) on skin erythema and pigmentation induced by UVB, UVA, visible light and solar simulated radiation. Phytother Res. 2003;17(2):141-6. [Crossref] [PubMed] 

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Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com