Hypericin, in St. John’s wort

Hypericin from St. John s wort is another phenolic compound with multiple rings and multiple double bonds. This compound readily absorbs UV light and is a primary photosensitizing agent that will result in severe sunburn in species that either ingest the plant or come in contact with plant dust or leaf extracts. 

Schey, K.L., Patat, S., Chignell, C.E, Datillo, M., Wang, R.H., and Roberts, J.E. (2000) Photooxidation of lens alpha-crystallin by hypericin (active ingredient in St. John s wort). Photochem Pho-tohiol 72 200-2003. 

Gulick RM, McAuliffe V, Holden-Wiltse J, et al. Phase I studies of hypericin, the active compound in St. John s Wort, as an antiretroviral agent in... 

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%)... 

Roberts JE, Wang RH, Tan IP, Datillo M, Chignell CF. Hypericin (active ingredient in St. John s Wort) photooxidation of lens proteins. Abstracts of the 27th Annual Meeting of the American Society of Photobiology 1999 42S. 

As an illustration, consider the extraction of hypericins from St. John s wort herb shown in Figure 11.18. This extraction test gives an equilibrium constant of 0.26 and 70% solvent remaining in the wet marc. If we assume that the raw material contains 0.15% hypericins, and the incoming solvent has no hypericins, then ... 

One way to confirm whether St. John s wort can help with depressive symptoms is to analyze its pharmacological action in the brain. With this information, we can then assess whether the herb may be acting in ways similar to other antidepressants. For many years, scientists believed that the active ingredient of St. John s wort was a substance called hypericin, thus St. John s wort remedies were often standardized by their hypericin content. However, recently other components of the herb s flowers and leaves have also been shown to produce pharmacological action in the brain, such as flavonoids (substances reputed to have anti-depressant and anti-anxiety actions). Thus it is most likely that several chemicals in St. John s wort work in conjunction to bring about therapeutic changes. 

Until recently, quality of drug preparations based on hypericum has been standardized by the hypericin(s) content (0.3%), determined by spectrophotometric measurements [22,38]. For this reason, distribution of hypericin and related constituents in St. John s Wort has been extensively studied. It has been found that hypericin is present in all the aerial parts of the plant, particularly in its flowers and buds. Accumulation of the protohypericins is however higher in the fresh plant material [22,39-42]. 

A commoniy reported drug-dietary suppiement interaction is between St. John s Wort and FiiV protease inhibitors, ieading to drug resistance and treatment faiiure. St. John s wort is a popuiar dietary suppiement often used for depression. Of the two substances found in St. John s wort, hypericin and hyperforin, hyperforin appears to be the main constituent, with in vitro seieotive serotonin reuptake inhibitor (SSRi) activity (see Chapter 21). Hyperforin aiso appears to be the more potent inducer of CYP3A enzymes based on in vitro and in vivo studies. 

Hypericin and pseudohypericin (Fig. 21) are naphthodianthrones and occur in St. John s wort Hypericum perforatum, Clusiaceae). These dark-red compounds are accumulated in glands on the margin oiK perforatum leaves and petals. It was assumed for a long time that they represent the antidepressant principle in extracts of St. John s wort. Recently, however, it became evident that the prenylated acylphloroglucinols hyperforin and adhyperforin are responsible for most of the pharmacological effects. 

It is being recognized increasingly that regulation can have a positive impact on laboratory productivity.36 System suitability testing has been proposed as superior to and supplemental to calibration in the UV-VIS detector.37 Large variations in both response factor and in relative response factors were observed on different instruments. Even on the same instrument, UV-VIS spectra can be extremely dependent on solution conditions, as was observed in a separation of hypericin, the antidepressant extract of St. John s wort.38... 

Some herbs are standardized for several active constituents, while others are standardized to a single active ingredient. St. John s wort is standardized to contain 0.3% hypericin, whereas ginkgo is standardized to contain 24% flavone glycosides and 6% ter-pene lactones. However, standardizing an herb product to one or more plant component(s) that are identifiable by assay may be incorrect. Many herbalists believe that the whole plant contributes to the efficacy and that there are many unknown active compounds in each plant [6]. 

St. John s wort is usually well tolerated, but insomnia, dizziness, fatigue, restlessness, GI upset, constipation, dry mouth, and allergy are reported as possible side effects. Hypomania has also been reported in several cases, and rarely, photosensitivity can be a problem following high doses hypericin seems to be the component responsible for the photosensitivity. Sun-induced neu-... 

A multicenter trial comparing more appropriate doses of imipramine (75 mg twice daily, N = 167) and St. John s wort extract (250 mg twice daily standardized to 0.2% hypericin, N = 157) showed no difference in efficacy after 6 weeks of treatment. However, St. John s wort seemed to reduce anxiety symptoms more often than imipramine and was better tolerated (Woelk, 2000). A study including 240 participants compared St. John s wort with fluoxetine in mild to moderate depression and also concluded that efficacy of both treatments was comparable (Schrader, 2000). These results have been replicated in a smaller trial us-... 

It is not possible to discuss pharmacokinetics when the active compound or compounds of St. John s wort are not known. The half-life of hypericin and hyperforin have been estimated at between 6 and 9 hours, with peak plasma concentrations at about 2-3 hours after administration. Some of the ingredients of Hypericum extracts are metabolized in the liver. 

The adult dosage of St John s wort traditionally recommended for treating depression is 300 mg of plant extract orally three times daily (plant extracts are usually standardised to 0.3% hypericin). There are no data about optimal dosage in young people. Clinicians often start with half the adult dose and increase the amount up to 300 mg three times daily after 3 or 4 weeks if the herb is well tolerated and there is no improvement. Clinical experience shows this regime results in few unwanted effects in the young. 

Of particular concern is that this inconsistency in product and active constituent occurs even within the same batch. As part of a clinical study with St. John s wort. Hall et al. analyzed 10 capsules of St. John s wort from the same lot (lot 13207) and found the mean total weight to be 444 mg (4.6% CV) versus 300 mg as stated on the label. In addition, the dosage form was supposed to be standardized to contain 900 pg of hypericin, but the mean content was found to be 840 pg (6.6% CV). There was also variability of the hyperforin content (mean 11 mg and 5.7 /o CV), which was not stated on the label (21). Our experience (Lam YWF, unpublished data) with two random capsules from one batch of kava-kava also showed the same extent of undesirable variance the total content of the pharmacologically active kavalactone was 47.3 mg in one capsule and 39.4 mg in the second one. 

St. John s wort and some individual constituents of the preparations have been administered orally, topically, and intravenously in various pharmaceutical formulations, including tinctures, teas, capsules, purified components, and tablets. These botanical preparations of St. John s wort are prepared from plant components (i.e., flowers, buds, and stalk) whose content of the wide array of structurally diverse bioactive constituents may differ (Table 1 and Fig. 2). Many commercial tablet and capsule formulations of St. John s wort are standardized using the ultraviolet absorbance of the naphtho-dianthrones, hypericin, and pseudohypericin, to contain 0.3% hypericin content. Thus, a 300 mg dose of St. John s wort contains approximately 900 pg hypericin per dose. Despite the standardization of dosage forms... 

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