Pharmacological Toxicological Effects

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The active component of St. John's wort is not known. It is composed of many different compounds. The concentrations of these chemicals vary from brand to brand and batch to batch. Hyperforin, hypericin, and pseudohypericin are considered by most to be the major active ingredients. Hypericin, pseudohypericin, isohypericin, protohypericin, protopseudohypericin, and cyclopseudohypericin are all anthraquinone derivatives (naphthodianthrones) (1-5). Hyperforin and adhyperforin are both prenylated phorolucinols (2,3). The flavonoids that are present include kaempferol, quercetin, luteolin, hyperoside, isoquercitrin, quercitrin, rutin, hyperin, hyperoside, I3-II8-biapigenin, 1,3,6,7-tetrhydroxyxanthone, and amentoflavone (2,3,5). The phenols consist of caffeic, chlorogenic, p-coumaric, ferulic, p-hydroxy-ben-zoic, and vanillic acids (3). The volatile oils include methyl-2-octane, n-nonane, methyl-2-decane and n-undecane, a- and P-pinene, a-terpineol, geraniol, myrcene, limonene, caryophyllen, and humulene (3). Other chemicals that are found in St. John's wort include tannins, organic acids (isovalerianic, nicotinic, myristic, palmitic, stearic), carotenoids, choline, nico-tinamide, pectin, ^-sitosterol, straight-chain saturated hydrocarbons, and alcohols (3). Most of these agents are found in other plants that do not possess antidepressant activity, which has led to most of the research being con centrated on the naphthodianthrones and hyperforin, which are only found in a few species.

5.1. Neurological Effects

There have been many clinical trials studying the effectiveness of St. John's wort in the treatment of depression. By the spring of 2002, there were 34 controlled trials including more than 3000 patients. Most of these trials included patients with mild to moderate depression and used the Hamilton Rating Scale of Depression (HAMD) to measure efficacy (6). Schulz compared the results of all of the trials since 1990. Nine of the 11 placebo-controlled trials showed a significant difference in the HAMD scores favoring hypericum, and a trend favoring hypericum was demonstrated in the other two. Linde also compared clinical trials with hypericum, and came to the conclusion that hypericum was superior to placebo in mild to moderate depression (7). When compared with the synthetic antidepressants, there was one trial with amitriptyline, four with imiprimine, two with fluoxetine, two with sertraline, one with bromazepam, and one with maprotiline. Of these trials, hypericum was equal to or superior to all of them except amitriptyline (6). In two trials comparing hypericum in major depression (participants with HAMD scores of at least 20), hypericum failed to show any improvement over placebo or other antidepressants (8,9). One randomized, controlled, double-blind, noninferiority trial that has been published since the Schulz review compared 900 mg/day of St. John's wort vs 20 mg/day of paroxetine in adult patients with acute major depression (HAMD score >22). Using the HAMD to assess efficacy, it was found that St. John's wort was at least as effective as paroxetine and was better tolerated (10).

Although the results from trials in patients with mild to moderate depression appear encouraging in their support of St. John's wort, there are limitations. First, the longest duration of these trials was 56 days and several of the trials were as short as 28 days. Also, most of the trials used relatively low doses of synthetic antidepressants. Finally, two of the trials did not state the exact number of responders, making the results somewhat questionable.

The exact mechanism of action responsible for St. John's wort's neurological effects is not known. Additionally, it is not known if any one chemical constituent is responsible for its activity or if it is a combination of multiple components. It is known that the extracts of H. perforatum appear to inhibit the synaptic uptake of several neurotransmitters including norepinephrine, serotonin (5-HT), and dopamine (3,11-13). Rats that were fed high doses of hypericum extracts standardized to flavonoids (50%), hypericin (0.3%), and hyperforin (4.5%) were shown to have dose-dependent enhanced 5-HT levels in all brain regions. Norepinephrine levels were increased in the dien-cephalon and brain stem, but not in the cortex, and higher levels of hypericum were needed. Dopamine levels were only increased in the diencephalon region with doses similar to those required for increased levels of norepinephrine (12). Cott demonstrated that hypericum extracts had affinity for adenosine, y-aminobutyric acid (GABA)-A, GABA-B, benzodiazapine, and monoamine oxidase (MAO) types A and B receptors (3). However, with the exception of GABA-A and GABA-B receptors, it is unlikely that the concentrations required to produce a physiological effect can be reached (3). Other studies have shown that hypericum extracts do not have high affinity for GABA-A and -B (5). Additionally, H. perforatum extracts downregulate P receptors and upregulate 5-HT2 receptors in the frontal cortex when given to rats (3,11). Hypericum extract standardized to flavonoids (50%), hypericin (0.3%), and hyperforin (4.5%) was shown to inhibit the release of interleukin-6 (IL-6) in vitro (14,15). IL-6 levels have been shown to be increased in patients with depression (14). It is thought that IL-6 induced stimulation of corticotropin-releasing hormone, adrenocorticotropic hormone, or cortisol may be responsible for increased depression (5). Also, using the rat forced-swimming model for depression, high doses of the extract was shown to improve depression in wild-type rats but had no effect in rats that were IL-6 knockouts (IL-6 -/-). The wild-type mice had a significantly greater increase in 5-HT in the diencephalon portion of the brain compared to the IL-6 -/mice. This finding indicates that IL-6 may be necessary to have an antide-pressant response to hypericum (14). Hypericum extract was shown to inhibit the enzyme dopamine-P-hydroxylase (D^H), and its inhibition is 200 times stronger than the inhibition by pure hypericin, suggesting that hyperi-cin is not the component responsible. D^H is the enzyme that catalyzes the conversion of dopamine into norepinephrine; thus St. John's wort may increase dopamine levels in the brain while lowering norepinephrine (16). High concentrations of hypericum extracts inhibit catechol-O-methyltransferase (COMT) activity (5). Consumption of a single dose of 2700 mg of St. John's wort extract was found to significantly increase plasma growth-hormone levels and decrease prolactin levels in human males (3).

It was once thought that hypericin was the main active ingredient in St. John's wort. In 1994, it was reported that hypericin inhibited MAO-A (11). Further studies have shown that hypericin and pseudohypericin do not inhibit MAO-A, and hypericum extracts only inhibit MAO at extremely high concentrations (5). Furthermore, hypericin did not display a significant (>25%)

inhibition of norepinephrine, dopamine, or 5-HT uptake sites, nor did it display high affinity to 5-HT, adenosine, adrenergic, benzodiazepine, dopamine, or GABA receptors (5,13). Hypericin was found to have high (>30%) levels of inhibition of nonselective muscarinic cholinergic receptors, 5-HT1A receptors and nonselective a receptors (5,17). Butterweck also has shown that hypericin and pseudohypericin have significant activity at D3- and D4-dopamine receptors, and that hypericin has significant activity at P-adrener-gic receptors (18).

Most evidence now implicates hyperforin as the main component responsible for the neurological activity of St. John's wort. Hyperforin has been shown to inhibit synaptic reuptake of 5-HT, dopamine, norepinephrine, GABA, l-glutamate, and acetylcholine (3,11,13,19). It is a potent uptake inhibitor of 5-HT, dopamine, norepinephrine, and GABA with 50% inhibition concentrations (IC50) of approx 0.05-2 ^g/mL (13). It has been shown that hyperforin increases the intracellular level of sodium, which may be directly responsible for its effect on 5-HT reuptake (11). Hyperforin was also shown to strongly inhibit D1- and D5-dopamine receptors and weakly inhibit binding to the opioid receptor h8 (18). Adhyperforin exists as a component in St. John's wort in approx one-tenth the concentration of hyperforin; but it, too, was found to be a potent uptake inhibitor of 5-HT, dopamine, and norepinephrine at lower IC50 values. Another factor that supports hyperforin's role as the active ingredient is that it is the major lipophilic constituent in hypericum extract, allowing it to cross the blood-brain barrier more easily (20).

Pseudohypericin has been shown to be a corticotropin-releasing factor (CRF)X receptor antagonist. CRF has been implicated as a pathogenic factor in affective disorders, with elevated levels that are normalized after treatment with antidepressants found in the cerebrospinal fluid of patients with depression. CRF acts on CRF1 receptors in the pituitary gland to stimulate the release of adrenocoticotropic hormone, which stimulates the release of glu-cocorticoid stress hormones from the adrenal glands (19). It is possible that St. John's wort's activity comes from pseudohypericin's ability to block the CRF1 receptor.

Amentoflavone is a biflavonoid with some pharmacological activity that may contribute to the activity of St. John's wort. It was found to significantly inhibit binding at 5-HT1d, 5-HT2c, D3-dopamine, 8-opiate, and benzodiazepine receptors (18).

Along with depression, hypericum has been studied in SAD. There have been two studies in which participants received 300 mg St. John's wort three times daily with or without bright-light therapy either for 4 or 8 weeks. In both studies there were significant reductions in HAMD scores or SAD scores, but no statistically significant difference in scores between the groups that received light therapy and those that did not (3).

A study using rats to measure the anxiolytic activity of Hypericum was conducted with efficacy being measured by several means. In this study, rats were given either Hypericum extract 100 or 200 mg/kg or lorazepam 0.5 mg/ kg. Using the open-field observation test and the maze test to measure anxiety, the Hypericum treatment groups showed anxiolytic efficacy and were superior to placebo, whereas the lorazepam was either equivalent to or superior to the Hypericum groups. With respect to social interaction, both treatment groups with Hypericum increased the amount of time the animals spent in social interactions with respect to control animals. Lorazepam-treated rats were comparable to the higher dose Hypericum group (21).

Obsessive-compulsive disorder (OCD) is a neurological disorder that affects 1.2-2.4% of the population (22). Drugs that inhibit 5-HT uptake are often used to treat OCD, with limited results. In a 12-week, open-label study,

13 people were treated with 450 mg of Hypericum standardized to 0.3% hypericin twice daily. Efficacy was measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Of the 13 members, 12 completed the trial, with an average reduction in their Y-BOCS scores of 7.42 from baseline, which is comparable to the results in studies using antidepressants. Additionally, five out of 12 patients rated themselves as much or very much improved, six out of 12 were minimally improved, and one noted no change. Interestingly, although the patients' average HAMD scores were a subclinical 6.09 at baseline, they dropped significantly to 1.91 at the end of the study (22).

Hypericum has also been studied for its effect on sleep. In a small trial,

14 females were given 300 mg Hypericum three times daily for 4 weeks, given a 2-week washout period, then given placebo for 4 weeks. The continuity of sleep, onset of sleep, intermittent wake-up phases, and total sleep were not improved. There was, however, a significant increase in deep sleep (stage 3 and 4, slow wave) that was shown by analysis of electroencephalogram activities (23). Thus, Hypericum may be able to improve sleep quality.

Somatoform disorders are a group of diseases that include the complaint of physical pain, which lead the patient to believe they have a physical disease, though none can be found by medical investigation (24). A study was conducted where 151 patients received either Hypericum 300 mg twice daily or placebo. Efficacy was measured using the Hamilton Anxiety Scale, subfactor somatic anxiety (HAMA-SOM). After 6 weeks, the average HAMA-SOM

decreased from 15.39 to 6.64 in the Hypericum arm and from 15.55 to 11.97 in the placebo arm, which was statistically significant, demonstrating the superiority of St. John's wort over placebo (24).

5.2. Antimicrobial Effects

St. John's wort has been used topically for wound healing for hundreds of years. Antibacterial properties have been reported as early as 1959, with hyperforin found to be the active component. Using multiple concentrations, it was discovered that no hyperforin dilutions had antimicrobial effects on Gram-negative bacteria or Candida albicans. There was, however, growth inhibition for all of the Gram-positive bacteria tested, some with the lowest dilution concentration of 0.1 |g/mL. Hyperforin was also shown to be effective at inhibiting methacillin-resistant Staphylococcus aureus (25).

Along with antibacterial properties, it has also been reported that both the hypericin and pseudohypericin components of St. John's wort have antiviral properties (2,26). In vitro studies showed antiviral activity against cytomegalovirus, Herpes simplex, human immunodeficiency virus (HIV) type I. Influenza virus A, moloney murine leukemia virus, and sindbis virus (2,3). Hypericin and pseudohypericin are thought to work by inhibiting viral replication via disruption of the assembling and processing of intact virions from infected cells. Mice coinjected with 150 |g of hypericin/pseudohypericin and the Friend virus had a 100% survival rate at 240 days whereas all control mice that were only injected with the virus were dead by day 23. Animals treated with lower doses (10 and 50 | g) were also protected, but not to the same degree (27). In an in vitro study, HeLa cells carrying HIVcat transcriptional units were incubated at concentrations of 25, 50, and 100 |g/mL of hypericin and 100 |g/mL of Ginkgo biloba, then exposed to ultraviolet (UV) light. It was found that hypericin inhibited the UV-induced HIV gene expression by 50, 81, and 88% correlating with the 25, 50 100 |g/mL concentrations when compared to control cells (g2). G. biloba inhibited the UV-induced HIV gene expression by 19% (28). The first study with St. John's wort in people with HIV was halted because of phototoxicity; further studies are on the way (2). When the first study in patients with AIDS was stopped, no significant improvements were seen in CD4 counts, HIV titer, HIV-RNA copies, or HIV p24 antigen levels (29). Flavonoid and catechins in St. John's wort have been shown to have some activity against influenza virus (3).

5.3. Mutagenicity

Quercetin, a flavonoid component of St. John's wort and several other medicinal plants, has been implicated as a mutagen. However, St. John's wort aqueous ethanolic extract showed no mutagenic effects in mammalian cells. Tests used included the HGPRT (hypoxanthine guanidine phosphoribosyl transferase) test, the UDS (unscheduled DNA synthesis) test, the cell transformation test using Syrian hamster embryo cells, the mouse-fur spot test, and the chromosome aberration test using Chinese hamster bone marrow cells (30).

5.4. Neuropathic Pain

Neuropathic pain is commonly treated with tricyclic antidepressants. Although generally efficacious, these drugs do have the potential to cause serious side effects. A crossover trial was conducted in which participants received St. John's wort standardized to 2700 of hypericin per day or placebo for 5 weeks, with a 1-week washout period between treatments. Patients rated several types of pain on a scale of 1-10. A total of 47 patients completed the trial, which showed a trend toward lower total pain with the St. John's wort treatment; however, it was not statistically significant. There was also a trend toward people reporting moderate to complete pain relief during their treatment with St. John's wort. When the study population was further broken down into patients with and without diabetes, it was found that in the 18 participants with diabetes, there was still a trend toward lower total pain and a significant reduction in lancinating pain, whereas in the 29 participants without diabetes, there was no significant differences or trends in any pain scores. Interestingly, 25 participants preferred the St. John's wort treatment arm, 16 preferred placebo, and six did not have a preference (31).

5.5. Inflammation/Asthma

There are many articles that address the role of St. John's wort in inflammation. As previously mentioned, St. John's wort is an inhibitor of IL-6, which is an important cytokine involved in inflammation (14,15). Additionally, hyperforin was found to inhibit cyclooxygenase (COX)-1 and 5-lipoxygenase (5-LO), key enzymes in the formation of proinflammatory eicosanoids. Moreover, it inhibited both enzymes at IC50 concentrations of 0.09 to 3 pM, which is close to the plasma concentrations achieved with standard dosing. Hyperforin was three times more potent then aspirin in its ability to inhibit COX-1 and almost equipotent to zileuton in its ability to inhibit 5-LO. Hyperforin did not significantly inhibit COX-2, 12-LO, or 15-LO enzymes (32). St. John's wort's ability to act as a 5-LO inhibitor could lead to a future role in asthma.

Another way that St. John's wort may reduce inflammation is by reducing inducible nitric oxide synthase (iNOS), which is increased in the early phases of inflammation. Nuclear factor-kB (NF-kB) and signal transducer and activator of transcription-1a (STAT-1a) are both implicated in inducing iNOS leading to the production of nitric oxide (NO), which is produced in large amounts near areas of inflammation. St. John's wort was found to inhibit STAT-1a, thereby reducing both iNOS and NO formation. Surprisingly, St. John's wort did not inhibit NF-kB, which was shown in earlier reports to be inhibited by quercetin, a component of St. John's wort (33).

5.6. Atopic Dermatitis

After it was found that St. John's wort, and more specifically hyperforin, has an inhibitory effect on epidermal langerhan cells, there was speculation that it may treat atopic dermatitis. A 4-week trial was conducted in which 21 patients with mild to moderate atopic dermatitis were treated twice daily with a cream standardized to 1.5% hyperforin on one side of their body and placebo on the other side. The primary end point of the study was severity scoring of atopic dermatitis (SCORAD) index, based on extent and intensity of erythema, papulation, crust, excoriation, lichenification, and scaling. Among the 18 participants that completed the study, the SCORAD index fell from a baseline score of 44.9 to 23.9 in the hyperforin group. The SCORAD index also fell from 43.9 to 33.6 in the placebo group. These results show statistically significant superiority of hyperforin cream over placebo, with no difference in skin tolerance to the two treatments. Of note, a secondary end point of the study showed a reduction of skin colonization with S. aureus with both hyperforin and placebo, with a trend toward better antibacterial activity with hyperforin cream (34). Although these results are positive, further studies should be conducted comparing hyperforin to corticosteroids in the treatment of atopic dermatitis.

5.7. Antioxidant

Free radicals are highly reactive molecules that have been implicated in cardiovascular and neurodegenerative disease. Hunt et al. generated superoxide radicals in both cell-free and human placental tissue to determine if St. John's wort has antioxidant qualities. They then tested St. John's wort samples that were standardized to either hypericin or hyperforin. In cell-free studies, both samples had a prooxidant effect at a 1:1 concentration. Both showed an inverse dose-related relationship in their antioxidant effect at concentrations from 1:2.5 to 1:20, with 1:20 having the greatest antioxidant effect in both groups. St. John's wort standardized to hypericin was superior in its antioxi-dant properties compared with hyperforin. Both were shown to be significant antioxidants in human placental vein tissue at a 1:20 dilution, the only concentration tested owing to results in the cell-free experiments.

5.8. Premenstrual Syndrome

There are numerous accounts of anecdotal evidence supporting the use of St. John's wort for premenstrual syndrome (PMS) (36). One open, uncontrolled study was conducted to determine the efficacy of St. John's wort in treating PMS. The primary outcome was measured by a daily symptom checklist of 17 symptoms rated on a scale of 0 to 4 based on the Hospital Anxiety and Depression (HAD) scale and modified Social Adjustment Scale (SAS-M) broken down into four subscales: mood, behavior, pain, and physical. A total of 25 women were selected to participate in the study in which they received 300 mg hypericum standardized to 900 |g hypericin daily. The results from the daily symptoms survey after the first cycle show a statistically significant reduction from the baseline value of 128.42 to 70.11. After the second cycle, there was a further reduction to 42.74. Of the four subscales, St. John's wort had the greatest improvement on the mood subscale (57%) and the least improvement on the physical subscale (35%). Of the individual symptoms, crying (92%) and depression (85%) were improved the most with treatment, and food cravings and headaches were improved the least (36).

5.9. Tumor Growth Inhibition

Hypericin, as mentioned earlier, is a fluorescent photosensitizer. When subjected to UV light, hypericin produces singlet oxygen, a nonradical oxygen species, which is highly reactive and cytoxic (37). In vitro studies with hypericin have shown significant growth inhibition in various human malignant cells, and in vivo studies demonstrate that it accumulates in bladder tumor cells when injected intravesically (37,38). In vivo studies were conducted in rats with transitional cell carcinoma of the bladder. Rats who were given hypericin IV and then photo-irradiated had their tumors eliminated in 15 days. Further studies could demonstrate success in human models with lower toxicity than current therapies such as bacillus Calmette-Guerin immu-notherapy (37). It is also thought that other agents present in St. John's wort have cytotoxic qualities. When human erythroleukemic cells (K562) (human chronic myelogenous leukemia) were incubated with purified hypericin in the dark, there was only a weak inhibitory effect on cell growth and no apop-totic effect (39). When K562 cells were incubated with various extracts of Hypericum, there was significantly more growth inhibition and apoptosis (38,39). Extracts of Hypericum that were high in flavonoid content and low in hyperforin content had significantly greater growth-inhibitory activity compared to extracts with similar hypericin content, but low flavonoid and high hyperforin content. This supports earlier work that flavonoids have antiproliferative effects on malignant cell lines. Additionally, when the same extracts that were incubated in the dark were incubated with 7.5 J/cm2 light activation, the IC50 values were lowered by roughly half, further demonstrating the phototoxic effects of hypericin (38). The mechanism of action of hypericin appears to be a combination of inhibition of protein kinase C, free-radical induction, release of mithochondrial cytochrome-c, and the activation of procaspase-3 (39,40). The flavonoids also appear to increase caspase activity and release of cytochrome-c (39).

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