Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Commercially available St. John's wort (Hypericum perforatum) extracts, preparations that are used in the treatment of depression, were examined for the potential to inhibit human cytochrome P450 (CYP) enzyme activities, specifically CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Crude extracts demonstrated inhibition of each of these five enzymes, with CYP2D6, CYP2C9, and CYP3A4 being more sensitive than CYP1A2 and CYP2C19. Extracts were fractionated by HPLC, and each of the fractions was tested for inhibition of these five CYPs to identify individual constituents with inhibitory activity. Several fractions were shown to possess inhibitory activity, including the fractions containing hyperforin (the putative active antidepressant constituent), I3,II8-biapigenin, and hypericin. Hyperforin and I3,II8-biapigenin were isolated from the extract, and inhibition constants for the five CYP activities were measured. In addition, three other constituents, hypericin, quercetin, and chlorogenic acid, were tested for inhibitory activity toward the CYP enzymes. The flavonoid compound I3,II8-biapigenin was shown to be a potent, competitive inhibitor of CYP3A4, CYP2C9, and CYP1A2 activities with K(i) values of 0.038, 0.32, and 0.95 microM, respectively. Hyperforin was a potent noncompetitive inhibitor of CYP2D6 activity (K(i) = 1.5 microM) and competitive inhibitor of CYP2C9 and CYP3A4 activities (K(i) = 1.8 and 0.48 microM, respectively). Hypericin also demonstrated potent inhibition of several CYP activities. These in vitro data indicate that St. John's wort preparations contain constituents that can potently inhibit the activities of major human drug-metabolizing enzymes and suggest that these preparations should be examined for potential pharmacokinetic drug interactions in vivo.
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PMID:Inhibition of human cytochrome P450 enzymes by constituents of St. John's Wort, an herbal preparation used in the treatment of depression. 1087 Dec 99

Extracts of Hypericum perforatum (St John's wort), such as LI 160, which are effective antidepressants have several active constituents. Their mode of action in depression, however, is unclear. In the present investigation, we assessed the effect of equivalent doses of LI 160 and two of its components, hypericin and hyperforin on serotonin (5-HT) and dopamine (DA)-mediated neuroendocrine responses in the rat. LI 160, hypericin and hyperforin significantly and equivalently increased plasma corticosterone. This effect was blocked by ketanserin but not WAY-100635, suggesting mediation via 5-HT2 receptors. LI 160 also lowered plasma prolactin and prevented the increase in plasma prolactin following haloperidol administration. Hyperforin had a similar but somewhat less pronounced effect. We conclude that LI 160, hypericin and hyperforin all increase 5-HT-mediated corticosterone release while LI 160 enhances DA-mediated inhibition of prolactin release. Hyperforin may contribute to the facilitatory effect of LI 160 on DA function, but hypericin does not.
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PMID:Acute effects of LI 160 (extract of Hypericum perforatum, St John's wort) and two of its constituents on neuroendocrine responses in the rat. 1119 53

Interactions between neurotransmitter receptors involved in the pathophysiology of depression, anxiety and ethanol consumption and two extracts (hydromethanolic and lipophilic extracts obtained with hypercritical CO2) from Hypericum Perforatum L or St. John's wort (SJW) and three constituents (hyperforin, hypericin and biapigenin) were evaluated by in vitro binding assays. The two extracts, tested at 10 microg/ml, did not inhibit ligand binding at the following receptors: serotonin 5-HT6 and 5-HT7, benzodiazepine, sigma and neuropeptide Y (NPY) Y1 and Y2 receptors. The hydromethanolic extract, but not the lipophilic extract, interacted with GABA(A) receptors (IC50 5.5 microg/ml), while both interacted with the dopamine (DA) transporters, albeit with high IC50 values (24.5 and 12.9 microg/ml, respectively). Biapigenin (1 microg/ml, 2 microM) inhibited ligand binding at benzodiazepine receptors only (IC50: 2 microM). Hyperforin (1 microg/ml, 2 microM) only inhibited [3H]WIN-35,428 binding to DA transporters, although the IC50 (5 microM) was higher than the IC50 found for inhibition of the synaptosomal DA reuptake (0.8 microM). This finding extended the same observation previously described for the 5-HTergic system to the DAergic system, confirming that the inhibition of monoamine reuptake is due to a different mechanism than that of synthetic antidepressants. Hypericin showed micromolar affinities for both NPY-Y1 and Y2 receptors and for sigma receptors (IC50 3-4 microM). These hypericin activities might be of interest because NPY and sigma receptors have been associated with anxiety disorders, depressive illnesses and ethanol consumption. However, they were present at relatively high hypericin concentrations, and were also light-dependent (i.e. the IC50 values increased when binding assays were carried out in the dark). Thus, our in vitro binding results may suggest that either the pharmacological effects of SJW are due to other molecules than hypericin or hyperforin (other constituents or active metabolites), or that the mechanism of action is different from those that have been considered up to now.
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PMID:In vitro binding studies with two hypericum perforatum extracts--hyperforin, hypericin and biapigenin--on 5-HT6, 5-HT7, GABA(A)/benzodiazepine, sigma, NPY-Y1/Y2 receptors and dopamine transporters. 1151 75

Along with traditional pharmacotherapies, extracts of Hypericum perforatum L. (St. John's wort) are used in the treatment of mild to moderately severe depression. Hypericum is a nonspecific inhibitor of the neuronal uptake of monoamines (serotonin, 5-HT; noradrenaline, NA; dopamine, DA) as well as GABA and glutamate. Hypericum extracts have been shown to be active in several different "animal models for antidepressant drugs". As one of a large number of chemical constituents, the phoroglucinol derivative hyperforin might be an important "antidepressant component" of hypericum. However, the exact role of neurochemical mechanisms underlying in vivo actions of hypericum and hyperforin are not well defined. In the present study, we compared the effects of hypericum, hyperforin and hyperforin-free hypericum and the three conventional antidepressants paroxetine, imipramine and desipramine using the passive avoidance (PA) task in the rat. The 5-HT-releasing compound p-chloroamphetamine (PCA), which operates through the 5-HT neuronal transporter, was used to reveal the potential in vivo effects on 5-HT uptake mechanisms. To examine the ability of the test-compounds to enhance noradrenaline (NA) transmission in vivo, subeffective doses of scopolamine were used. Taken together, our results suggest that (1) hypericum given at high doses can probably affect the neuronal 5-HT uptake mechanisms in a manner more reminiscent of TCAs than SSRIs; (2) similar to TCAs and SSRIs, hypericum and hyperforin are active in the scopolamine test. Hyperforin appears to play a major role in the action of hypericum in this model. Both 5-HT and NA might concomitantly contribute to the effects of different antidepressants in the "low-dose scopolamine" model; (3) hypericum might enhance both 5-HT and NA transmission in forebrain limbic brain circuits important for mood control, which could underly its antidepressant effects. However, the relative contribution of different constituents and exact mechanisms of action require further evaluation.
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PMID:Effects of Hypericum perforatum (St. John's wort) on passive avoidance in the rat: evaluation of potential neurochemical mechanisms underlying its antidepressant activity. 1151 84

Hyperforin, hypericin and pseudohypericin are the main ingredients of St. John's wort extract, which is available over the counter for treatment of mild to moderate depression. To facilitate clinical studies we developed two sensitive HPLC methods for determination of hypericin/pseudohypericin and hyperforin, respectively, in human plasma samples. The achieved limits of quantitation of 0.25 ng/ml for hypericin and pseudohypericin and 10 ng/ml for hyperforin were low enough to allow determination of pharmacokinetic parameters of the substances. Following liquid-liquid extraction of human plasma the samples were separated by isocratic reversed-phase HLPC and analyzed using fluorimetric detection for hypericin/pseudohypericin and UV detection for hyperforin.
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PMID:Determination of hyperforin, hypericin, and pseudohypericin in human plasma using high-performance liquid chromatography analysis with fluorescence and ultraviolet detection. 1181 6

Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of mild to moderate depression. Hyperforin, a constituent of St. John's wort, is known to inhibit the sodium-dependent uptake of catecholamines and amino acids into synaptic nerve endings, probably by interference with mechanisms controlling the synaptic sodium concentration. Because de novo synthesis of acetylcholine (ACh) is dependent on sodium-dependent high-affinity choline uptake, we studied the effect of hyperforin on choline (Ch) uptake in vitro and on striatal ACh release in vivo using microdialysis. In rat brain synaptosomes, hyperforin inhibited high-affinity choline uptake with an IC(50) of 8.5 microM, whereas low-affinity uptake was not affected. Local infusion of hyperforin (100 microM) via the dialysis probe caused a delayed reduction of ACh release and a concomitant increase of Ch levels. Infusion of a lower concentration of hyperforin (10 microM), however, increased striatal ACh release and lowered Ch levels. Systemic administration of hyperforin (1-10 mg/kg i.p.) led to therapeutic plasma levels of hyperforin and caused a significant elevation of striatal ACh release. Behavioral testing revealed a reduction of locomotor activity in mice treated with high-dose (10 mg/kg) hyperforin. We conclude that low doses of hyperforin stimulate striatal ACh release by an unknown mechanism, whereas high doses inhibit synaptic choline uptake and ACh release. The results are discussed with respect to the therapeutic use of St. John's wort in patients with neurodegenerative disorders.
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PMID:Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort. 1196 Oct 77

For many years, hypericum extracts have been used in the treatment of depressive disorders. The therapeutical use of these extracts has been predominantly justified for a long time by the clinical evidence of efficacy and only partly by results of scientific studies. The aim of the present investigation is to perform a meta-analysis of the placebo- and verum-controlled studies carried out till now, to examine the relevance of hyperforin and hypericin for the clinical efficacy of St. John's Wort, to discuss biochemical and pharmacoendocrinological studies investigating the mechanism of action, and to describe side effects and interactions of hypericum extracts. In particular during recent years, methodologically quite sophisticated studies have been performed. The comprehensive evaluation of all studies available suggests a significant superiority of hypericum extracts over placebo, despite the negative results of two recently published American trials, and a therapeutic efficacy comparable to that of synthetic antidepressants in mildly to moderately depressed patients. Furthermore, it has been suggested in preclinical and clinical studies that the content of hyperforin but not of hypericin decisively contributes to the antidepressant efficacy of hypericum extracts. Hyperforin has been demonstrated in biochemical investigations--like synthetic antidepressants--to inhibit the reuptake of the neurotransmitters norepinephrine, serotonin, and dopamine. Hypericum extracts can be regarded as well tolerated, and they extend the variety of pharmacotherapeutical options in the treatment of depression, especially in outpatients. However, interactions in combination treatments are possible by interference with the cytochrom P450 system, thereby changing plasma levels of other medications.
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PMID:[Hypericum perforatum extract in treatment of mild to moderate depression. Clinical and pharmacological aspects]. 1221 22

Hyperforin is one of the most important active components in St. John's wort (Hypericum perforatum), a botanical dietary supplement used as an alternative treatment modality for mild to moderate depression. A solid-phase extraction (SPE) and an isocratic high-performance liquid chromatography (HPLC) analysis with ultraviolet (UV) detection were developed to determine hyperforin in human plasma samples. Benzo[k]fluoranthene was used as an internal standard. The absolute recovery for hyperforin was more than 89% for plasma concentrations ranging from 25 to 500 ng/ml. The linearity of calibration curves, inter-day and intra-day relative standard deviations were investigated. The limit of detection (LOD) of hyperforin was 4 ng/ml in plasma and the limit of quantitation (LOQ) was 10 ng/ml. Hyperforin concentrations in human plasma following St. John's wort administration were analyzed. The result suggests that this method is rapid, sensitive, reproducible and capable of quantitative analysis of hyperforin plasma concentrations.
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PMID:Determination of hyperforin in human plasma using solid-phase extraction and high-performance liquid chromatography with ultraviolet detection. 1238 88

The nuclear xenobiotic receptor PXR is activated by a wide variety of clinically used drugs and serves as a master regulator of drug metabolism and excretion gene expression in mammals. St. John's wort is used widely in Europe and the United States to treat depression. This unregulated herbal remedy leads to dangerous drug-drug interactions, however, in patients taking oral contraceptives, antivirals, or immunosuppressants. Such interactions are caused by the activation of the human PXR by hyperforin, the psychoactive agent in St. John's wort. In this study, we show that hyperforin induces the expression of numerous drug metabolism and excretion genes in primary human hepatocytes. We present the 2.1 A crystal structure of hyperforin in complex with the ligand binding domain of human PXR. Hyperforin induces conformational changes in PXR's ligand binding pocket relative to structures of human PXR elucidated previously and increases the size of the pocket by 250 A(3). We find that the mutation of individual aromatic residues within the ligand binding cavity changes PXR's response to particular ligands. Taken together, these results demonstrate that PXR employs structural flexibility to expand the chemical space it samples and that the mutation of specific residues within the ligand binding pocket of PXR tunes the receptor's response to ligands.
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PMID:2.1 A crystal structure of human PXR in complex with the St. John's wort compound hyperforin. 1257 55

This study in mice investigated whether hyperforin accounts for the inductive effects on cytochrome P4503A enzymes of St. John's wort extracts (SJW; Hypericum perforatum), one of the most popular herbal preparations because of its alleged activity in mild to moderate depression. A hydroalcoholic extract containing 4.5% hyperforin was given at a dose of 300 mg/kg, bis in die (b.i.d.), for 4 and 12 days. Hyperforin, its main phloroglucinol component, was given as dicyclohexylammonium (DCHA) salt (18.1 mg/kg, b.i.d.) on the basis of its content in the extract, to ensure comparable exposure to hyperforin. The extract increased hepatic erythromycin-N-demethylase (ERND) activity, which is cytochrome P450 enzyme (CYP) 3A-dependent, about 2.2-fold after 4 days of dosing, with only slightly greater effect after 12 days (2.8 times controls). Hyperforin too increased ERND activity within 4 days, much to the same extent as the extract (1.8 times the activity of controls), suggesting that it behaves qualitatively and quantitatively like the extract as regards induction of CYP3A activity. This effect was confirmed by Western blot analysis of hepatic CYP3A expression. Exposure to hyperforin at the end of the 4-day treatment was still similar to that with SJW extract, although it was variable and lower than after the first dose in both cases, further suggesting that hyperforin plays a key role in CYP3A induction by the SJW extract in the mouse. Standardization of the extracts based on the hyperforin content can be proposed for further evaluation of their potential action on first-pass metabolism and clearance of coadministered CYP3A substrates.
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PMID:Hyperforin contributes to the hepatic CYP3A-inducing effect of Hypericum perforatum extract in the mouse. 1285 35


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