Pharmacological activity hypericins

St. John s wort, also known as hypericum, contains a variety of constituents that may contribute to its pharmacologic activity. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved. Commercial formulations are usually prepared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried. 

Two molecular mechanisms for the interactions have been established. First, both hypericin and hy-perforin, two of the pharmacologically active constituents of the herb, cause induction of the enzyme CYP3A4 which is responsible for much of the metabolism of many commonly used drugs. Giving SJW to patients also taking the immunosuppressant, cyclosporine, which is metabolized primarily by CYP3A4, has led to near-rejection of transplanted organs as cyclosporine plasma concentrations fell due to increased metabolism. The same mechanism has led to reduced efficacy of indinavir in patients... 

The leafy parts of the herb contain naphthodi-anthrones (e.g., hypericin), flavonoids (e.g., quercetin), and phloroglucinols (e.g., hypaphorine). Although this herb is now commonly standardized for its hypericin content, it appears that its other constituents may also be just as pharmacologically active. 

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 Our experience (Lam YWF, unpublished data) with two random capsules from one batch of kava-kava also showed the same extent of undesirable variance the total content of the pharmacologically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. 

The pharmacological activity of SJW extracts has recently been reviewed (55-58). Recent reports have shown that the antidepressant activity of Hypericum extracts can be attributed to the phloroglucinol derivative hyperforin (59-62), to the naphthodianthrones hypericin and pseudohypericin (18,63-65), and to several flavonoids (66-69). The role and the mechanisms of action of these different compounds are still a matter of debate. But, taking these previous findings together, it is likely that several constituents are responsible for the clinically observed antidepressant efficacy of SJW. 

The pharmacological activities of the various constituents of St.John s wort have been studied extensively. Hyperforin appears to be the major bioactive constituent and it acts in several ways serving as a neurotransmitter reuptake inhibitor with a broad selectivity, as a ligand for the pregnane X receptor, and as an antibacterial and antitumor agent. It also has a rapid effect on amyloid precursor protein processing, indicating a possible role in the prevention of Hypericin and the flavonoid constituents may have... 

The drug contains peculiar chemical constituents such as naphtodianthrones (hypericins), acylphloroglucinols (hyperforins), flavonol glycosides (quercetin derivatives) and biflavones [9] and all the metabolites as a whole seem to contribute to its pharmacological activity. Current use of St. John s Wort is mainly for the treatment of mild to moderate depression [10,3] and drug extracts for antidepressant applications have become increasingly popular. 

Other pharmacological activities described for Hypericum extracts include diuretic [185]. antioedematous [186] and anthelminthic properties [187]. In yeast cells highly diluted hypericin 1 has been reported to stimulate respiratory activity [1]. Moreover, general roborant and tonic effects of small doses of hypericin 1, reflected in an increased vitality and growth rate of farm and laboratory animals, have repeatedly been described [1]. 

This herbal product has the most data available to support its usefulness as an antidepressant. Nevertheless, only minimal information is available about its pharmacology and its relative risk-benefit ratio. At least seven different biologically active chemicals have been isolated from crude extracts of hypericum. Several are ubiquitous in the plant kingdom. The exceptions are hypericin and pseudohypericin, which have been assumed to be responsible for any antidepressant activity of this product. Nevertheless, there is the potential for one or more of these seven compounds and their metabolites to mediate desired or undesired effects, particularly when used in combination with other medications (i.e., herb-drug interactions). 

COMT hypothesis. According to this hypothesis. St. John s wort increases the levels of catecholamines at the brain synapses by inhibiting their inactivation by oxidative deamination (MAOl) and by catechol functionalization (catechol-0-methyltransferase [COMTl). Recent studies have shown that hypericins possess such activities only at pharmacologically excessive concentrations. If true, these effects at normal doses are small and do nothing to alleviate depression. Other hypotheses suggest hormonal effects or effects on the dopaminergic system. Hyperforin has become a candidate for the major antidepressant constituent of St. John s wort. 

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. 

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