ISSN 1214-0287 (on-line)
ISSN 1214-021X (printed)

Volume 1 (2003), No 2, p 61-70

The chemistry, pharmacology, and toxicology of the biologically active constituents of the herb Hypericum perforatum L.

Jiri Patocka

Address: Jiri Patocka, Katedra toxikologie, Vojenska lekarska akademie, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic and Faculty of Health and Social Sciences, Ceske Budejovice, Czech Republic

Received 3rd June 2002.
Published online 26th February 2003.

Full text article (pdf)

St. John's wort (Hypericum perforatum) has been used as a medical herb for over 2000 years. Over the past two decades, its application as a standardized plant extract for treating depression has undergone rigorous scientific investigation, and its effectiveness has been shown in studies comparing it with other commonly used antidepressants and placebos. Safety and tolerability studies have revealed that Hypericum preparations have better safety and tolerability profiles than synthetic antidepressants. The indications for St. John's wort preparations are mild or moderate depression. The mechanism of the antidepressant action of Hypericum extract is not fully known. The view of the chemical composition and pharmaceutical a toxicological properties of biologically active substances of Hypericum perforatum is the main purpose of this paper.

Hypericum perforatum; antidepressant; pharmacology; toxicology

Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS, Pruess HG: Free radicals and grape seed proanthocyanidin extract: importance in human health and disease prevention. Toxicology 148:187-197, 2000.

Baureithel KH, Buter KB, Engesser A, Burkard W, Schaffner W: Inhibition of benzodiazepine binding in vitro by amentoflavone, a constituent of various species of Hypericum. Pharm Acta Helv 72:153-157, 1997.

Bennet GJ, Lee HH: Xanthones from the Guttiferae. Phytochemistry 28:967-998, 1989.

Bennett DA Jr., Phun L, Polk JF, Voglino SA, Zlotnik V, Raffa RB: Neuropharmacology of St. John's Wort (Hypericum). Ann Pharmacother 32:1201-1208, 1989.

Berghoefer R, Hoelzl J: Biflavonoids in Hypericum perforatum; Part 1. Isolation of I3,II8-biapigenin. Planta Med 53:216-217, 1987.

Berghoefer R, Hoelzl J: Isolation of I3',II8-biapigenin (amentoflavone) from Hypericum perforatum. Planta Med 55: 91, 1989.

Bladt S, Wagner H: Inhibition of MAO by fractions and constituents of hypericum extract. J Geriatr Psychiatry Neurol 7, Suppl 1:S57-59, 1994.

Brantner A, Kartnig T, Quehenberger F: Vergleichende phytochemische Untersuchungen an Hypericum perforatum L. und Hypericum maculatum Crantz. Scient Pharm 62:261-276, 1994.

Brockman H: Photodynamisch wirksame Pflanzenfarbstoffe. In: Zechmeister L: Fortschr Chem Org Naturstoffe, Bd. XIV, Springer Verlag, Wien 1957.

Brockmoller J, Reum T, Bauer S, Kerb R, Hubner W-D, Roots I: Hypericin and pseudohypericin: Pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry 30, Suppl:94-101, 1997.

Cardona L, Fernandez I, Pedro JR, Serrano A: Xanthones from Hypericum reflexum. Phytochemistry 29:3003-3006, 1990.

Chatterjee SS, Bhattacharya SK, Wonnemann M, Singer A,. Muller WE: Hyperforin as a possible antidepressant component of hypericum extracts. Life Sci 63:499-510, 1998a.

Chassevent F: Chlorogenic acid, physiological and pharmacological activity (Article in French) Ann Nutr Aliment 23, Suppl 1: 1-14, 1969.

Chatterjee SS, Biber A, Weibezahn C: Stimulation of glutamate, aspartate and gammaaminobutyric acid release from synaptosomes by hyperforin. Pharmacopsychiatry 34, Suppl 1:S11-S19, 2001.

Chatterjee SS, Noldner M, Koch E, Erdelmeier C: Antidepressant activity of hypericum perforatum and hyperforin: the neglected possibility. Pharmacopsychiatry 31, Suppl. 1:7-15, 1998b.

Cellarova E, Daxnerova Z, Kimakova K, Haluskova J: The variability of the hypericin contents in the regenerants of Hypericum perforatum. Act Biotechnol 14:267-274, 1994.

De Bruyne T, Pieters L, Witvrouw M, De Clercq E, Vanden Berghe D, Vlietinck AJ: Biological evaluation of proanthocyanidin dimers and related polyphenols. J Nat Prod 62:954-958, 1999.

Falk H, Schmitzberger W: On the nature of "soluble" hypericin in Hypericum species. Monatshefte Chem. 123:731-739, 1992.

Ghelardini C, Galeotti N, Mazzanti G: Local anaesthetic activity of monoterpenes and phenylpropanes of essential oils. Planta Med 67:564-566, 2001.

Giese A: Hypericism. Photochem Photobiol Rev 5:229-255, 1980.

Haeberlain H, Tschiersch K-P, SchAfer HL: Flavonoids from Leptospermum scoparium with affinity to the benzodiazepine receptor characterized by structure activity relationships and in vivo studies of a plant extract. Pharmazie 49:912-922, 1994.

Haeberlain H, Tschiersch K-P, Stock S, Hoelzl J: Johanniskraut (Hypericum perforatum L.). Teil 1, Nachweis eines weiteren Naphthodianthrons. Pharm Ztg Wiss 137:169-174, 1992.

Hegnauer R: Chemotaxonomie der Pflanzen, Vol. VII. BirkHAuser Verlag, Berlin 1989.

Jurgenliemk G, Nahrstedt A: Phenolic compounds from Hypericum perforatum. Planta Med 68:88-91, 2002.

Kim HK, Son KH, Chang HW, Kang SS, Kim HP: Amentoflavone, a plant biflavone: a new potential anti-inflammatory agent. Arch Pharm Res 21:406-410, 1998.

Klusa V, Germane S, Noldner M, Chatterjee SS: Hypericum extract and hyperforin: memory-enhancing properties in rodents. Pharmacopsychiatry, Suppl 1:S61-S69, 2001.

Koch E, Chatterjee SS: Hyperforin stimulates intracellular calcium mobilisation and enhances extracellular acidification in DDT1-MF2 smooth muscle cells. Pharmacopsychiatry 34, Suppl 1:S70-S73, 2001.

Maisenbacher P, Kovar K-A: Adhyperforin: A homologue of hyperforin from Hypericum perforatum. Planta Med 58:291-293, 1992.

MacGregor JT: Genetic toxicology of dietary flavonoids. Prog Clin Biol Res 206:33-43, 1986.

Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D, Paladini AC: Overview - flavonoids: a new family of benzodiazepine receptor ligands. Neurochem Res 22:419-425, 1997.

Melzer R, Fricke U, Holzl J: Vasoactive properties of procyanidins from Hypericum perforatum L. in isolated porcine coronary arteries. Arzneim-Forsch /Drug Res. 41:481-483, 1991.

Morales MA, Lozoya X: Calcium-antagonist effects of quercetin on aortic smooth muscle. Planta Med 60:313-317, 1994.

Mori H, Kawabata K, Matsunaga K, Ushida J, Fujii K, Hara A, Tanaka T, Murai H: Chemopreventive effects of coffee bean and rice constituents on colorectal carcinogenesis. Biofactors 12:101-105, 2000.

Muller WE, Singer A, Wonnemann M: Hyperforin - antidepressant activity by a novel mechanism of action. Pharmacopsychiatry 34, Suppl 1:S98-S102, 2001.

Nahrstedt A, Butterweck V: Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 30, Suppl 2:129-134, 1997.

Nielsen H, Arends P: Structure of the xanthone lignoid kielcorin. Phytochemistry 17:2040-2041, 1978.

Nielsen M, Frokjaer S, Braestrup C: High affinity of the naturally-occuring biflavonoid, amentoflavon, to brain benzodiazepine receptors in vitro. Biochem Pharmacol 37:3285-3287, 1988.

Niesel S, Schilcher H: Vergleich der Freisetzung von Hypericin und Pseudohypericin in Abhangigkeit verschiedener Extraktionsbedingungen. Arch Pharm 323:755, 1990.

Peebles KA, Baker RK, Kurz EU, Schneider BJ, Kroll DJ: Catalytic inhibition of human DNA topoisomerase IIalpha by hypericin, a naphthodianthrone from St. John's wort (Hypericum perforatum). Biochem Pharmaco 62:1059-1070, 2001.

Pietta P, Gardana C, Pietta A: Comparative evaluation of St. John's wort from different Italian regions. Farmaco 56:491-496, 2001.

Poginski B, Westendorf J, Prosenc N, Kuppe M, Marquard H: Johannis kraut (Hypericum perforatum L.). Genotoxicitat bedingt durch den Quercetingehalt. Dtsch Apoth Ztg 128:1364-1366, 1988.

Raffa RB: Screen of receptor and uptake-site activity of hypericin component of St. John's wort reveals sigma receptor binding. Life Sci 62:PL265-PL270, 1988.

Rueff J, Laires A, Borba H, Chaveca T, Gomes MI, Halpern M: Genetic toxicology of flavonoids: the role of metabolic conditions in the induction of reverse mutation, SOS functions and sister-chromatid exchanges. Mutagenesis 1:179-183, 1986.

Scalbert A: Antimicrobial properties of tannins. Phytochemistry 30:3875-3883, 1991.

Scalbert A, Deprez S, Mila I, Albrecht AM, Huneau JF, Rabot S: Proanthocyanidins and human health: systemic effects and local effects in the gut. Biofactors 13:115-120, 2000.

Schempp CM, Kirkin V, Simon-Haarhaus B, Kersten A, Kiss J, Termeer CC, Gilb B, Kaufmann T, Borner C, Sleeman JP, Simon JC: Inhibition of tumour cell growth by hyperforin, a novel anticancer drug from St. John's wort that acts by induction of apoptosis. Oncogene 21:1242-1250, 2002.

Scholz E: Pflanzliche Gerbstoffe. Dtsch Apoth Ztg 134:3167-3179, 1994.

Sparenberg B, Demisch BL, Hoelzl J: Untersuchungen uber antidepressive Wirkstoffe von Johanniskraut. Phar Ztg Wiss 6/138:50-54, 1993.

Stavric B: Quercetin in our diet: From potent mutagen to probable anticarcinogen. Clin Biochem 27:245-248, 1994.

Stock S, Hoelzl J: Ist Johanniskraut phototoxisch? Med Mod Pharm 14:304-306, 1991.

Takahashi I, Nakanishi S, Kobayashi ., Nakano H, Suzuki K, Tamaoki T: Hypericin and pseudohypericin specifically inhibit protein kinase C: possible relation to their antiretroviral activity. Biochem Biophys Res Commun 165:207-1212, 1989.

Takhtajan A: Evolution und Ausbreitung der Blutenpflanzen. G. Fischer, Stutgart 1973.

Thiede HM, Walper A: Inhibition of MAO and COMT by hypericum extracts and hypericin. J Geriatr Psychiatry Neurol 7, Suppl 1:S54-S56, 1994.

Vandenbogaerde AL. Kamuhabwa A, Delaey E, Himpens BE, Merlevede WJ, de Witte PA: Photocytotoxic effect of pseudohypericin versus hypericin. J Photochem Photobiol B45:87-94, 1998.

Viola H, Wolfman C, Destein ML, Wasowski C, Pena C, Medina JH, Paladini AC: Isolation of pharmacologically active benzodiazepine receptor ligands from Tilia tomentosa. J Ethnopharmacol 44:47-53, 1994.

Volz HP: Controlled clinical trials of hypericum extracts in depressed patients - an overview. Pharmacopsychiatry 30, Suppl 2:72-76, 1997.

Wall ME, Wani MC, Hughes TJ, Taylor H: Plant antimutagens. In: Kuroda Y, Shankel DB, Waters MD: Antimutagenesis and anticarconogenesis mechanism. II. Plenum Publ. Corp, New York 1990, p. 61-78.

Wu QL, Wang SP, Du LJ, Yang JS, Xiao PG: Xanthones from Hypericum japonicum and H. henryi. Phytochemistry 49:1395-1402, 1998.

Ocak Z, Acar M, Gunduz E, Gunduz M, Demircan K, Uyeturk U, Ozlu T. Effect of hypericin on the ADAMTS-9 and ADAMTS-8 gene expression in MCF7 breast cancer cells. Eur Rev Med Pharmacol Sci. 17: 1185-1190, 2013.

Peron AP, Mariucci RG, de Almeida IV, Dusman E, Mantovani MS, Vicentini VEP. Evaluation of the cytotoxicity, mutagenicity and antimutagenicity of a natural antidepressant, Hypericum perforatum L. (St. John's wort), on vegetal and animal test systems. BMC Compl Alter MErd. 13, Art No 97, 2013.

Cheng YB, Fazary AE, Lin YC, Lo IW, Ong SC, Chen SY, Chien CT, Lin YJ Lin WW, Shen YC. Hyperinakin, a new anti-inflammatory phloroglucinol derivative from Hypericum nakamurai. Natur Prod Res. 27: 727-734, 2013.

Cirak C, Radusiene J, Camas N, Caliskan O, Odabas MS. Changes in the contents of main secondary metabolites in two Turkish Hypericum species during plant development. Pharmaceut Biol. 51: 391-399, 2013.

Cirak C, Radusiene J, Stanius Z, Camas N, Caliskan O, Odabas MS. Secondary metabolites of Hypericum orientale L. growing in Turkey: variation among populations and plant parts. Acta Physiol Plantarum. 34: 1313-1320, 2012.

Mendoza-Urbina FA, Gutierrez-Miceli FA, Ayora-Talavera TR, Rincon-Rosales R. Scarification of seeds of Hypericum silenoides Juss. and its effect on germination. Gayana Botanica. 69: 1-6, 2012.

Camas N, Radusiene J, Stanius Z, Caliskan O, Cirak C. Secondary Metabolites of Hypericum leptophyllum Hochst., an Endemic Turkish Species. Sci World J. Art No: 501027, 2012.

Assadi A, Zarrindast MR, Jouyban A, Samini M. Comparing of the Effects of Hypericin and Synthetic Antidepressants on the Expression of Morphine-Induced Conditioned Place Preference. Iran J Pharm Res. 10: 619-626, 2011.

Bhatia A, Arora S, Singh B, Kaur G, Nagpal A. Anticancer potential of Himalayan plants. Phytochem Rev. 10: 309-323, 2011.

Kizil G, Kizil M, Ceken B, Yavuz M, Demir H. Protective ability of ethanol extracts of Hypericum scabrum L. and Hypericum retusum Aucher against the protein oxidation and DNA damage. Int J Food Prop. 14: 926-940, 2011.

Anyzewska M, Kowalczuk A, Lozak A, Jablczynska R, Fijalek Z. Determination of total hypericins in St. John's wort and herbal medicinal product. ActaPol Pharm. 67: 586-592, 2010.

Tonk FA, Giachino RRA, Sonmez C, Yuce S, Bayram E, Telci I, Furan MA. Characterization of various Hypericum perforatum clones by hypericin and RAPD analyses. Int J Agric Biol. 13: 31-37, 2011.

Bejaoui A, Boulila A, Messaoud C, Rejeb MN, Boussaid M. Genetic diversity and population structure of Hypericum humifusum L. (Hypericacae) in Tunisia: Implications for conservation. Plant Biosystems. 144: 592-601, 2010.

Oluk EA, Orhan S, Karakas O, Cakir A, Gonuz A. High efficiency indirect shoot regeneration and hypericin content in embryogenic callus of Hypericum triquetrifolium Turra. Afr J Biotechnol. 9: 2229-2233, 2010.

Caccia S, Gobbi M. St. John's Wort Components and the Brain: Uptake, Concentrations Reached and the Mechanisms Underlying Pharmacological Effects. Curr Drug Met. 10: 1055-1065, 2009.

Odabas MS, Radusiene J, Cirak C, Camas N. Models of estimation of the content of secondary metabolites in some Hypericum species. Pharm Biol. 47: 1117-1122, 2009.

Geng XT, Ren P, Pi GP, Shi RF, Yuan Z, Wang CH. High selective purification of flavonoids from natural plants based on polymeric adsorbent with hydrogen-bonding interaction. J Chromatogr A. 1216: 8331-8338, 2009.

Ayan AK, Radusiene J, Cirak C, Ivanauskas L, Janulis V. Secondary metabolites of Hypericum scabrum and Hypericum bupleuroides. Pharm Biol. 47: 847-853, 2009.

Cirak C, Ivanauskas L, Janulis V, Radusiene J. Chemical constituents of Hypericum adenotrichum Spach, an endemic Turkish species. Nat Prod Research. 23: 1189-1195, 2009.

Toker Z. Variation of total hypericin, phenolic and flavonoid compounds in Hypericum triquetrifolium during its phenological cycle. Pharm Biol. 47: 285-288, 2009.

Mccue PP, Phang JM. Identification of Human Intracellular Targets of the Medicinal Herb St. John's Wort by Chemical-Genetic Profiling in Yeast. J Agric Food Chem. 56: 11011-11017, 2008.

Odabas MS, Radusiene J, Cirak C, Camas N. Prediction models for the phenolic contents in some Hypericum species from Turkey. Asian J Chem. 20: 4792-4802, 2008.

Kacar O, Goksu E, Azkan N. Effects of morphogenetic and diurnal variability on the hypericin content in St. John's Wort (Hypericum perforatum L.). African J Biotechnol. 7: 2163-2168, 2008.

Cirak C, Radusiene J, Camas N. Pseudohypericin and hyperforin in two Turkish Hypericum species: Variation among plant parts and phenological stages. Biochem Syst Ecol. 36: 377-382, 2008.

Ayan AK, Cirak C. Hypericin and pseudohypericin contents in some Hypericum species growing in Turkey. Pharm Biol. 46: 288-291, 2008.

Cirak C, Radusiene J, Arslan B. Variation of bioactive substances in Hypericum montbretii during plant growth. Nat Prod Res. 22: 246-252, 2008.

Cirak C, Radusiene J, Janullis V, Lvanauskas L, Arslan B. Chemical constituents of some Hypericum species growing in Turkey. J Plant Biol. 50: 632-635, 2007.

Cirak C, Radusiene J. Variation of hyperforin in Hypericum monthretii during its phenological cycle. Nat Prod Res. 21: 1151-1156, 2007.

Jung HJ, Park K, Lee IS, Kim HS, Yeo SH, Woo ER, Lee DG. S-Phase accumulation of Candida albicans by anticandidal effect of amentoflavone isolated from Selaginella tamariscina. Biol Pharm Bull. 30: 1969-1971, 2007.

Cirak C, Radusiene J, Ivanauskas L, Janulis V. Variation of bioactive secondary metabolites in Hypericum origanifolium during its phenological cycle. Acta Physiologiae Plantarum. 29: 197-203, 2007.

Cirak C, Radusiene J, Janulis V, Ivanauskas L. Secondary metabolites in Hypericum perfoliatum: variation among plant parts and phenological stages. Bot Helv. 117: 29-36, 2007.

Cirak C, Radugien J, Karabuk B, Janulis V. Variation of bioactive substances and morphological traits in Hypericum perforatum populations from Northern Turkey. Biochem Syst Ecol. 35: 403-409, 2007.

Sosa S, Pace R, Bornancin A, Morazzoni P, Riva A, Tubaro A, Della Loggia R. Topical anti-inflammatory activity of extracts and compounds from Hypericum perforatum L. J Pharm Pharmacol. 59: 703-709, 2007.

Cirak C, Radusiene J, Karabuk B, Janulis V, Ivanauskas L. Variation of bioactive compounds in Hypericum perforatum growing in turkey during its phenological cycle. J Integrat Plant Biol. 49: 615-620, 2007.

Tsaplev YB, Vasil'ev RF. The nature of chemiluminescence of the photolyzed anthrone solutions. Russ J Phys Chem. 80: 795-798, 2006.

Cirak C, Ayan AK, Kevseroglu K. Direct and indirect regeneration of plants from internodal and leaf explants of Hypericum bupleuroides gris. J Plant Biol. 50: 4-28, 2007.

Ayan AK, Cirak C, Yanar O. Variations in total phenolics during ontogenetic, morphogenetic, and diurnal cycles in Hypericum species from Turkey. J Plant Biol. 49: 432-439, 2006.

Cirak C. Hypericin in Hypericum lydium Boiss. growing in Turkey. Biochem Syst Ecol. 34: 897-899, 2006.

Cirak C, Saglam B, Ayan AK, Kevseroglu K. Morphogenetic and diurnal variation of hypericin in some Hypericum species from Turkey during the course of ontogenesis. Biochem Syst Ecol. 34: 1-13, 2006.

Ang CYW, Hu LH, Heinze TM, Cui YY, Freeman JP, Kozak K, Luo WH. Instability of St. John's Wort (Hypericum perforatum L.) and degradation of hyperforin in aqueous solutions and functional beverage. J Agric Food Chem. 52: 6156-6164, 2004.