Active Components of St. John's Wort (Hypericum perforatum)
Introduction
Extracts of St. John's wort display antidepressant activity in mouse models of depression (1). Unfortunately, commercially available extracts of St. John's wort contain dramatically different amounts of biologically active components (2). Elucidating which components of a St. John's wort extract contribute to antidepressant activity would provide standardized formulations for the subsequent evaluation of clinical effectiveness.
Components of St. John's Wort
Biological compounds are extracted from the flowers and buds of St. John's wort (Hypericum perforatum) using various solvents, typically alcohols. Many components are hydrophobic and therefore, insoluble in water. Various techniques are used to physically separate the components of an extract. The solvent is evaporated and additional procedures are used to identify each compound. The components of St. John's wort have been identified as phenylpropanes, flavonol derivatives, biflavones, proanthocyanidins, xanthones, phloroglucinols, some amino acids, naphthodianthrones and essential oil constituents (3).
Receptor Binding of Compounds Isolated from St. John's Wort
A powerful technique to screen compounds for receptor binding activity was used to examine compounds derived from St. John's wort (4). The initial screen with a single high concentration of each compound resulted in numerous "hits" or matches with receptor targets. Subsequent competition binding experiments revealed how well each compound interacted with receptors (Ki values). The data document that four compounds displayed remarkably high binding affinities relative to reference drugs. The St. John's wort components (and receptor targets) include: hyperforin (dopamine D1 receptor), hypericin (dopamine D3 receptor), rutin (muscarinic M5 receptor), and amentoflavone (GABA receptor and delta opioid receptor). Hopefully, future versions of this unique screening assay will invoke a much larger representation of potential receptor targets. Nonetheless, the intriguing results provide additional candidate compounds for further functional analyses.
Summary and Future Directions
Although hyperforin and hypericin have received a great deal of attention, it is becoming clear that more than one component is required for the observed antidepressant activity of St. John's wort extracts (5). Rutin has been shown to contribute to the antidepressant activity of St. John's wort extracts in mouse models of depression (6). Amentoflavone (a diapigenin) is composed of two molecules of apiginen which has been shown to interact with GABA receptors and elicit an anti-anxiety (anxiolytic) response (7). Thus, future studies need to determine the pharmacology (agonist vs. antagonist) and behavioral effects of purified rutin and amentoflavone. The roles of muscarinic M5, GABA, and delta opioid receptor activities in mouse models of depression also warrant further investigation. It is hopeful that continued research with these and other natural compounds will lead to drug formulations that can be tested in clinical trials.
References
(1) Butterweck V, Wall A, Lieflander-Wulf U, Winterhoff H, Nahrstedt A (1997) Effects of the total extract and fractions of Hypericum perforatum in animal assays for antidepressant activity. Pharmacopsychiatry 30:117-24.
(2) Schulte-Lobbert S, Holoubek G, Muller WE, Schubert-Zsilavecz M, Wurglics M (2004) Comparison of the synaptosomal uptake inhibition of serotonin by St John's wort products. Journal of Pharmacy and Pharmacology 56:813-818.
(3) Nahrstedt A, Butterweck V (1997) Biologically active and other chemical constituents of the herb of Hypericum perforatum L. Pharmacopsychiatry 30129-34.
(4) Butterweck V, Nahrstedt A, Evans J, Hufeisen S, Rauser L, Savage J, Popadak B, Ernsberger P, Roth BL (2002) In vitro receptor screening of pure constituents of St. John's wort reveals novel interactions with a number of GPCRs. Psychopharmacology (Berlin) 162:193-202.
(5) Caccia S (2005) Antidepressant-like components of Hypericum perforatum extracts: an overview of their pharmacokinetics and metabolism. Current Drug Metabolism 6:531-43.
(6) Noldner M, Schotz K (2002) Rutin is essential for the antidepressant activity of Hypericum perforatum extracts in the forced swimming test. Planta Medica 68:577-80.
(7) Viola H, Wasowski C, Levi de Stein M, Wolfman C, Silveira R, Dajas F, Medina JH, Paladini AC (1995) Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects. Planta Medica 61:213-6.
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