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St. John's wort (Hypericum perforatum)


Synonyms / Common Names / Related Terms
Amber touch-and-heal, balm-of-warrior's wound, balsana, bassant, Blutkraut, bossant, Calmigen®, corancillo, dendlu, devil's scorge, Eisenblut, flor de São João, fuga daemonum, goatweed hartheu, heofarigo on, herba de millepertius, herba hyperici, Herrgottsblut, Hexenkraut, hierba de San Juan, hipericão, hipérico, hipericon, HP, isorhamnetin, Jarsin, Johanniskraut, klammath weed, Liebeskraut, LI 160, lord God's wonder plant, millepertius pelicao, perforate, pinillo de oro, PM235, pseudohypericin, rosin rose, SJW, SJW extract LI 160, St. John's wort WS 5572, STW 3-VI, tenturotou, Teufelsflucht, touch and heal, Walpurgiskraut (German), witcher's herb, WS 5572.



Mechanism of Action
Pharmacology:
  • Overview: St. John's wort cultivated for medicinal use is harvested upon flowering and is prepared from the aerial portions of the plant. Herbal preparations are then extracted with ethanol or methanol. Notably, the hyperforin, hypericin, and flavonol content may vary widely according to harvest time, plant quality, and region of origin.39 The apparent broad mechanism of St. John's wort is not fully understood, yet biologically active constituents may include hyperforin and adhyperforin (phloroglucinols), hypericin and pseudohypericin (naphthodianthrones), flavonoids, xanthones, oligomeric procyanidines, and amino acids.40,41 Methods for evaluation and standardization of the components are still under active investigation.42,43 St. John's wort's antidepressant activity may be mediated by the serotonergic (5-HT), noradrenergic (NE), and dopaminergic (DA) systems44,34,45,46,47,48, as well as via the neurotransmitters glutamate and γ-aminobutyric acid (GABA)14,35,49,50. Weak activity in vitro suggests a combination of multiple mechanisms51, several of which are presented in the following paragraphs.
  • Antimicrobial effects: MeOH, petroleum ether, CHCl3, and EtOAc extracts of the aerial parts of St. John's wort were assayed for antimicrobial activity. Growth inhibition was observed for the Gram-positive bacteria B. subtilis and B. cereus. The Hypericum extract obtained with EtOAc was the most active. The main constituents of this extract, as determined by HPLC analysis, were flavonoids, hypericins, and hyperforins. Incubation of the selected microorganisms with the pure chemicals resulted in a significant inhibition of their growth by hypericin, hyperforin, and its stable dicyclohexilammonium salt. Flavonoids appeared inactive.1
  • Antioxidant effects: In rats, administration of 1.4mg/kg of scopolamine impaired retrieval memory. This amnesia was associated with elevated MDA and reduced GSH brain levels. In naive rats, which had not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level or activity. Low concentrations of Hypericum extract displayed an inverse dose-related relationship of superoxide inhibition.1 Free radical-scavenging activity of Hypericum has been found to correlate with its flavonoid constituents, including hyperoside and quercetin.2,3
  • Anti-proliferative/anti-inflammatory effects: St. John's wort was found to inhibit the growth of, and induce apoptosis in, experimental leukemia and glioma cell lines.52,4 Similar apoptoic activity was observed in mouse tumor models.53 An immunosuppressive effect of hypericin was found in vitro, mediated by inhibition of arachidonic acid and interleukin-6 release, leukotriene B4, and interleukin-1α production.54,55 An immunosuppressive effect, including an inhibition of T-cell proliferation, was observed in vitro and in vivo in response to St. John's wort (in vivo, the effect of Hypericum ointment was compared with the immunosuppressive effect of solar-simulated radiation), which may provide a rationale for the treatment of inflammatory skin disorders with St. John's wort extracts.21 In vitro inhibition of free radical production has also been demonstrated in cell-free and human vascular tissue.3
  • Hyperforin can stimulate IL-8 expression in human intestinal epithelia cells (IEC) and primary hepatocytes. Hyperforin is also able to induce the expression of mRNA for ICAM-1. Hyperforin was shown to induce IL-8 mRNA through an SXR-independent transcriptional activation pathway. IL-8 induction by hyperforin required the activation of AP-1 but not the NF-kappaB transcription factor. Further study revealed that extracellular signal-regulated kinase 1 and 2 (ERK1/2) were required for the hyperforin-induced expression of IL-8.56 Extracts of St. John's wort strongly down-regulate mitogen-mediated tryptophan degradation in a dose-dependent manner. This effect seems to be based on a suppressive activity of H. perforatum on activated immunocompetent cells, resulting in a diminished production of IFN-gamma.57
  • The stable dicyclohexylammonium salt of hyperforin was shown to trigger an apoptosis-associated cytotoxic effect in murine and human tumor cells. Untransformed endothelial cells were only marginally affected. An inhibition of various proteinases instrumental to extracellular matrix degradation was also noted (leukocyte elastase, cathepsin G, and urokinase-type plasminogen activator). In mice that received intravenous injections of C-26 or B16-LU8 cells daily, intraperitoneal administration of hyperforin reduced inflammatory infiltration, neovascularization, lung weight, and size and number of experimental metastases.58
  • Hyperforin has been shown to target components within the G protein signaling cascades involved in the regulation of Ca2+ homeostasis, resulting in regulation of ROS generation and the release of leukocyte elastase from human isolated polymorphonuclear leukocytes.59 Hyperforin inhibited IL-6 release from human astrocytoma cells (U373MG) in vitro. In whole blood, however, hyperforin levels needed to inhibit IL-6 release are about one order of magnitude higher than the hyperforin levels measured in the plasma of rats or humans treated with pharmacologically active doses of St. John's wort or hyperforin.60
  • In vivo, hypericin treatment inhibited NF-kappaB caused accumulation of phosphorylated IkappaBalpha, decreased p50 protein levels, and induced cleavage of p65 protein in U373 and MCF-7 cells.61
  • Antiviral effects: A variety of in vitro studies have documented St. John's wort's antiviral properties.22,23,24,25,26,27,28,29,30,31 A photodynamic mechanism has been proposed for the mechanism of action of HIV inactivation.30,28,62
  • Drug metabolism: St. John's wort and hyperforin were observed to increase mRNAs for the drug metabolizing enzymes CYP3A4, CYP1A1, and CYP1A2, the flavin-containing monooxygenase FMO5, and of the multidrug resistance protein MRP2. CYP4F2 and the reduced nicotinamide adenine dinucleotide dehydrogenase NQO1 were down-regulated. Expression of genes mediating cholesterol biosynthesis was decreased, while facilitated glucose transporters and glycolysis genes were induced, indicating increased glucose metabolism. Changes of a considerable number of additional transcripts corresponded to reports on gene regulation by hypoxia. Endoplasmic reticulum stress-regulated genes involved in unfolded protein response and in protection of cells from apoptosis were down-regulated. Other calcium binding proteins were affected by both treatments, suggesting an increase in intracellular calcium.11
  • Electroencephalogram (EEG) findings: Electrophysiological studies have found enhanced striatal alpha-1 activity early after oral administration, which may indicate an interaction with serotonin reuptake; later increases in delta and beta-2 activity may be correlated with GABA binding and NMDA agonism.63 Enhanced activation in beta-2 regions had been previously reported.64 In a human study, increases in alpha-1, delta, and theta activity was found to increase with St. John's wort.65 It has been suggested that evaluations of EEG activity may provide more insight into the neurophysiology of St. John's wort than examinations of REM sleep.66 However, Sharpley reported that Hypericum increased latency to REM sleep similar to standard antidepressants.67,68
  • Monoamine oxidase inhibitor (MAOI) activity: Early work reported in vitro inhibition of monoamine oxidase (MAO) A and B by hypericin16, as well as other components, such as xanthon and flavonols19. Thiede and Walper found both MAO and catechol-o-methyltransferase (COMT) inhibition.20 Yet these authors, along with others17, concluded that the concentrations causing inhibition were not adequate to explain antidepressant activity. Cott reported hypericin lacked significant MAO inhibition at concentrations to 10mcM14, and based upon other findings, such as a pharmacokinetics study by Staffeldt et al.38, suggested that this inhibition may not be pharmacologically relevant.
  • Serotonin (5-HT), norepinephrine (NE), dopamine (DA) activities: It has been proposed that the activity of St. John's wort is occurs via inhibition of serotonin, norepinephrine, and dopamine synaptic reuptake.34,35,36,37 Müller reported that hyperforin is likely the active component; hyperforin approximated the molar efficacy of standard tricyclic antidepressants, with uniquely similar potency in serotonin, norepinephrine, and dopamine systems.34 Although not definitive, efficacy in behavioral paradigms of depression (learned helplessness, behavioral despair) has correlated with hyperforin content.69 Bhattacharya reported dose-dependent potentiation of serotonin-mediated animal behaviors, with greater effect in the hyperforin-enriched (38.8% hyperforin) CO2 extract. In contrast, the ethanolic extract (4.5% hyperforin) potentiated dopamine-mediated behaviors.45 In addition, significant down-regulation of B-receptor density and an increase in 5-HT2 receptors has been demonstrated in animal cortex following treatment with Hypericum extract.34 The number of both 5-HT1 A and 5-HT2 A receptors was significantly increased, by 50%, compared to controls in another report.70 In the Müller study, the effect on serotonergic receptors varied according to the extract; a methanolic extract led to a significant increase in receptor density, compared to a (nonsignificant) decrease in receptor density found with a hyperforin-enriched CO2 extract.34 A neuroendocrine study in healthy adults demonstrated an increase in cortisol with 600mg oral WS5570 extract, suggesting central norepinephrine or serotonin neurotransmitter activity. The authors posit that hyperforin plasma concentrations vary according to dose of extract and should be considered in evaluating biochemical and clinical activity.71
  • Other neurotransmitter biochemical effects: The mechanism of St. John's wort activity may be different from standard antidepressants.72 Monoamine inhibition may be noncompetitive, via sodium channels, such as enhancement of intracellular Na+ concentrations.18,49,50 Jensen has also suggested that a direct effect on known transporter sites may not be the mechanism.73 In this study, neither hyperforin nor adhyperforin inhibited binding of a cocaine analogue to the dopamine transporter. Benzodiazepine, adenosine, inositol triphosphate, GABA, N-methyl-D-aspartic acid14,15, and cholinergic receptor activity74 may also contribute to psychotropic effects. Likewise, St. John's wort has been found to affect nighttime melatonin levels, modulate cytokine expression55, increase cortisol71, inhibit sigma opioid receptor activity74 and antagonize naloxone44.
  • After seven days of treatment with St. John's wort, an increase was noted in the dopamine metabolite plasma dihydroxyphenylacetic acid.75 Wong et al. suggest that antidepressant treatment by St. John's wort may be due to changes in gene expression in a discrete brain region, based on the identification of common differentially regulated genes between St. John's wort and a conventional antidepressant (imipramine) in the rat hypothalamus.76

Pharmacodynamics/Kinetics:
  • Drug concentration levels: After oral administration of hyperforin 300mg, steady state plasma concentrations were approximately 100ng/mL.13
  • After long-term dosing of Hypericum extract (300mg three times daily), steady state was reached after four days.38
  • Time to peak: After single oral doses of 300, 900, and 1,800mg of Hypericum extract, the median maximal plasma levels were 1.5, 4.1, and 14.2ng/mL, respectively, for hypericin and 2.7, 11.7, and 30.6ng/mL, respectively, for pseudohypericin.38
  • In humans given 300mg extract (5% hyperforin), mean plasma concentration (Cmax) of hyperforin was 150ng/mL, 3.5 hours after oral administration.13
  • The maximum plasma concentration was reached after 3.5 hours after oral administration of 300mg of Hypericum.13
  • After single dose intake of 612mg dry extract of St. John's wort, the maximum plasma concentration of hypericin was 3.14ng/mL, and time to maximum concentration was 8.1 hours; for pseudohypericin the maximum plasma concentration was 8.50ng/mL with a time to maximum concentration of 3.0 hours; and for hyperforin, the maximum plasma concentration was 83.5ng/mL with a time to maximum concentration of 4.4 hours.77 Quercetin and isorhamnetin showed two peaks of maximum plasma concentration separated by about 4 hours. The maximum plasma concentration of quercetin was 47.7ng/mL and the time to maximum concentration was 1.17 hours; for isorhamnetin, the maximum plasma concentration was 7.6ng/mL, and the time to maximum concentration was 1.53 hours.
  • Area under the curve (AUC): After a single dose intake of 612mg dry extract of St. John's wort, the AUC(0-infinity) for Hypericum was 75.96 hours x ng/mL; for pseudohypericin, the AUC(0-infinity) was 93.03 hours x ng/mL; for hyperforin, AUC(0-max) was 1009.0 hours x ng/mL; for quercetin, the AUC(0-infinity) was 318.7 hours x ng/mL; and for isorhamnetin, the AUC(0-infinity) was 98.0 hours x ng/mL.
  • Administering 900 or 1,200mg of Hypericum extract resulted in lower maximum concentration and AUC values than those expected.13
  • Bioavailability: Systemic availability of hypericin and pseudohypericin after oral administration has been estimated at 14% and 21%, respectively.78
  • Distribution: A distribution half-life of three hours was noted for hyperforin.13
  • Metabolism: Based on animal study, hyperforin is metabolized in the liver by the hydroxylation pathway.79 Four major Phase I metabolites, including 19-hydroxyhyperforin, 24-hydroxyhyperforin, 29-hydroxyhyperforin, and 34-hydroxyhyperforin, were isolated.79
  • Cytochrome P450: St. John's wort is an inducer of cytochrome P450 enzymes, particularly the CYP3A4 family.9 Moore et al. demonstrated that St. John's wort (hyperforin) activates a regulator (pregnane X receptor) of CYP3A4 transcription and thereby induces expression of 3A4 in human liver cells.10 Bray et al. demonstrated induction of 3A and 2E1 in mice.7 Upon review, it was noted that St. John's wort may inhibit CYP3A4 acutely and then induce this enzyme with repeated administration.80,8 CYP2C9, 2D6, and 3A4 inhibition has also been reported in in vivo and in vitro study.5,6 A brief, three-day trial did not demonstrate a similar significant effect on 2D6 or 3A4 enzymes.33
  • P-glycoprotein: St. John's wort is known to induce cytochrome P450 (CYP) 3A4 and P-glycoprotein through pregnane X-receptor activation. It has been suggested that this may be accomplished through increased multidrug resistant receptor 1 (MDR1) messenger ribonucleic acid (mRNA) and increased P-glycoprotein levels in the duodenal mucosa, possibly influenced by the MDR1 genotype.81,32,8,12
  • Elimination half-life: The elimination half-life ranges from 24-36 hours for hypericin40; between 9-19.64 hours for hyperforin77; between 9 and 23.76 hours for hypericin77,13; 25.39 hours for pseudohypericin77; 4.16 hours for quercetin77; and 4.45 hours for isorhamnetin77.

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