Hyperforin inhibitors

Gey, C Kyrylenko, S Hennig, L., Nguyen, L.H., Biittner, A., Pham, H.D. et al. (2007) Phloroglucinol derivatives guttiferone G, aristoforin, and hyperforin inhibitors of human sirtuins SIRTl and SIRT2. Angewandte Chemie, 119, 5311-5314. 

Hyperforin, the major constituent in Hypericum perforatum (St. John s Wort), inhibits the enzymatic activity of 5-lipoxygenase and COX-1 in platelets, acts as a dual inhibitor of 5-lipoxygenase and COX-1, and might have some potential in inflammatory and allergic diseases connected to eicosanoids (32), Several Hypericum species are of medicinal value in Asia and the Pacific. One of these is Hypericum erectum Thunb., the potential of which as a source of 5-lipoxygenase is given here. 

Dana A, Ilse Z, Dingermann T, Muller WE, Steinhilber D, Werz O. Hyperforin is a dual inhibitor of cyclooxygenase-1 and 5-lipoxygenase. Biochem Pharmacol 2002 64 1767-1775. 

The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did. Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical 13 adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2) in a rodent model. 

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. 

Expression of ABCBl can be strongly upregulated via PXR after binding with ligands such as H IV-protease inhibitors [83] and hyperforin (the active compound of St. John s wort) [84]. 

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... 

Assays with extracts devoid of hypericin but with a high content of hyperforin as well as assays with pure hyperforin demonstrated that this metabolite can modulate the function of various neurotransmitters involved in depression, being a potent inhibitor of serotonin, dopamine, noradrenaline and GABA uptake with almost equal potency. Moreover, results from clinical studies evidenced that the antidepressant efficacy of Hypericum preparations correlates with their content of hyperforin [6,87],... 

In a specific work, it has been shown that chemical modification of hyperforin by acylation, oxidation and alkylation produce detrimental effects on the molecule activity as inhibitor of serotonin uptake [89], and the presence of the enolized cyclohexanedione moiety in its structure has been related to its efficacy on the re-uptake of neurotransmitters. 

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