Hypericin and pseudohypericin specifically inhibit protein kinase C: Possible relation to their antiretroviral activity

Takahashi, Isami; Nakanishi, Satoshi; Kobayashi, Eiji; Nakano, Hirofumi; Suzuki, Katsutoshi; Tamaoki, Tatsuya

doi:10.1016/0006-291x(89)92730-7

Cited by 210 publications

(101 citation statements)

References 15 publications

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“…The isoflavones daidzein and genistein (Table II), potent tyrosine kinase inhibitors (45,46), were only very weak 131 and 116 M, respectively). Because of their known inhibitory effect on protein kinases (47), pseudohypericin (Table III) and hypericin (Table IV) were also tested. Hypericin reduced the enzyme activity of IP3K very effectively already in absence of illumination (IC 50 , 170 nM).…”

Section: Resultsmentioning

confidence: 99%

Antiproliferative Plant and Synthetic Polyphenolics Are Specific Inhibitors of Vertebrate Inositol-1,4,5-trisphosphate 3-Kinases and Inositol Polyphosphate Multikinase

Mayr

Windhorst

Hillemeier

2005

Journal of Biological Chemistry

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1 an enzyme ubiquitously found in all mammalian tissues (1), plays a central role in the anabolic routes of inositol phosphates in vertebrate cells because it phosphorylates the second messenger Ins(1,4,5)P 3 as the starting substrate of these reactions. The IP3K family consists of three isoenzymes referred to as IP3K-A (2-4), IP3K-B (5), and IP3K-C (6) differing in their degree of activation by Ca 2ϩ -CaM, affinity for Ins(1,4,5)P 3 (reviewed in Ref. 7), tissue and intracellular distribution. IP3K-B is expressed in nearly all human tissues and is localized at actin filaments (8, 9) and the endoplasmic reticulum (9, 10) whereas IP3K-A was identified mainly in brain and testis (9, 11) and shows an exclusive F-actin localization (12). IP3K-C is also widely expressed in mammalian cells and in rat it was shown to shuttle actively between nucleus and cytoplasm (13). An additional Ins(1,4,5)P 3 kinase enzyme, inositol polyphosphate multikinase (IPMK), was identified in yeast, rat, man, and plants (14 -18). IPMK exhibits nuclear localization and evidently plays a role in nuclear InsP metabolism (16). In vertebrates, the Ins(1,3,4,5)P 4 product of these enzymes is the starting substrate to be metabolized by different InsP kinases and phosphatases leading to Ins(1,3,4,5,6)P 5 , InsP 6 and the pyrophosphorylated isoforms of InsP 5 and InsP 6 (19,20). InsP 6 is normally the most abundant InsP in eukaryotic cells and appears to be important in several processes; in yeast it is essential for intact vesicle structures (21), mRNA export (22, 23) and is involved in chromatin remodeling (24). For mammalian cells a stimulation of DNA repair (25), endocytosis (26), and exocytosis (27) in pancreatic ␤-cells, Ca 2ϩ channel activity (28, 29), an involvement in synaptic vesicle trafficking (30,31), and other effects were reported for InsP 6 (reviewed in Refs. 19 and 32).To ease studies of the importance of higher InsPs for cell proliferation or other cellular functions in vivo, one possible approach is to block their biosynthesis by pharmacological inhibition of IP3K isoforms and IPMK. Other approaches are knock-out or RNAi experiments shutting down enzymes generating Ins(1,3,4,5)P 4 or higher InsPs. An individual knock-out of IP3K-A in mice resulted in a very weak CNS phenotype in the former case (34). IP3K-B knockout revealed an essential role of the enzyme or its products for T-cell immunity (35). That deletion of the broadly expressed IP3K-B did not generate further phenotypes may be caused by rescue phenomena based on the fact that a total of four enzymes are able to convert Ins(1,4,5)P 3 to Ins(1,3,4,5)P 4 . These considerations led us to start a search for pharmacological IP3K and IPMK inhibitors. We first examined herbal and synthetic compounds belonging to the flavonoids, anthraquinones, coumarins, triphenylmeth-* This work was supported by Grants Ma989 and GRK 336 (to G. W. M.) from the Deutsche Forschungsgemeinschaft. The costs of publication of this article were defrayed in part by the payment of page charges. This articl...

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Section: Resultsmentioning

confidence: 99%

Antiproliferative Plant and Synthetic Polyphenolics Are Specific Inhibitors of Vertebrate Inositol-1,4,5-trisphosphate 3-Kinases and Inositol Polyphosphate Multikinase

Mayr

Windhorst

Hillemeier

2005

Journal of Biological Chemistry

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“…To clarify the cellular mechanism of SJW, we focused our attention on the molecular pathways modulated by hypericin. Enzyme assays performed on rat brain demonstrated that hypericin is a potent and selective inhibitor of the protein kinase C (PKC) (Takahashi et al 1989), enzyme highly involved in pain modulation (Velazquez et al 2007). PKC is a family of serine/ threonine kinases that are divided into three groups based on calcium and diacylglicerol dependence: conventional (α, βI, βII, γ), novel (δ, ε, η, θ), atypical (ζ, λ/ι) (Way et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Galeotti¹,

Ghelardini²

2012

Psychopharmacology

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Rationale Hypericum perforatum, popularly called St. John's wort (SJW), is a medicinal plant mainly used as antidepressant with a favorable safety profile than standard antidepressants. Some studies have also documented other SJW bioactivities, including pain modulation. Objectives The aim of this study was to demonstrate the capability of SJW to relieve nitric oxide (NO)-induced nociceptive hypersensitivity and identify the effective component. Methods Nociceptive hypersensitivity induced by administration of the NO donors nitroglycerin (GTN) and sodium nitroprusside (SNP) was assessed by cold and hot plate tests. The cellular pathways and molecular targets involved were investigated by Western blotting. Results GTN and SNP produced a prolonged allodynia and hyperalgesia in mice. A single oral administration of low doses of an SJW dried extract or purified hypericin reversed the NO donor-induced nociceptive behavior whereas hyperforin and flavoinoids were ineffective. Investigating into the cellular pathways involved, an increased CREB and STAT1 phosphorylation, and activation of NF-κB were detected within PAG and thalamus following NO donors' administration. These cellular events were prevented by SJW or hypericin. Since hypericin showed PKC blocking properties, a role of PKC as an upstream modulator of these transcription factors was hypothesized. NO donors increased expression and phosphorylation of protein kinase C (PKC) γ and ε isoforms, molecular events prevented by SJW or hypericin. Conclusions SJW reversed NO-induced nociceptive hypersensitivity through the blockade of a supraspinal signaling pathway involving a PKC-dependent CREB, STAT1 and NF-κB activation due to presence of hypericin. These data indicate SJW/hypericin as a therapeutic perspective for pain treatment.

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“…Hypericin displays light-induced activity against several types of viruses, including the human immunodeficiency virus (HIV), [9][10][11] as well as antiproliferative and cytotoxic effects on tumor cells. [12][13][14][15] Hypericin is also a potent antidepressant, 16,17 exhibits light-dependent inhibition of protein kinase C (PKC), which has been suggested to be a locus of its antiviral activity, 18 and is reported to possess numerous other types of biological behavior. [19][20][21] Hypericin, like other anticancer drugs, also induces apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Interaction of Glutathione S-Transferase with Hypericin: A Photophysical Study

et al. 2005

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The photophysics of hypericin have been studied in its complex with two different isoforms, A1-1 and P1-1, of the protein glutathione S-transferase (GST). One molecule of hypericin binds to each of the two GST subunits. Comparisons are made with our previous results for the hypericin/human serum albumin complex (Photochem. Photobiol. 1999, 69, 633−645). Hypericin binds with high affinity to the GSTs: 0.65 μM for the A1-1 isoform and 0.51 μM for the P1-1 isoform (Biochemistry 2004, 43, 12761−12769). The photophysics and activity of hypericin are strongly modulated by the binding protein. Intramolecular hydrogen-atom transfer is suppressed in both cases. Most importantly, while there is significant singlet oxygen generation from hypericin bound to GST A1-1, binding to GST P1-1 suppresses singlet oxygen generation to almost negligible levels. The data are rationalized in terms of a simple model in which the hypericin photophysics depends entirely upon the decay of the triplet state by two competing processes, quenching by oxygen to yield singlet oxygen and ionization, the latter of these two are proposed to be modulated by A1-1 and P1-1. The photophysics of hypericin have been studied in its complex with two different isoforms, A1-1 and P1-1, of the protein glutathione S-transferase (GST). One molecule of hypericin binds to each of the two GST subunits. Comparisons are made with our previous results for the hypericin/human serum albumin complex (Photochem. Photobiol. 1999, 69, 633-645). Hypericin binds with high affinity to the GSTs: 0.65 µM for the A1-1 isoform and 0.51 µM for the P1-1 isoform (Biochemistry 2004, 43, 12761-12769). The photophysics and activity of hypericin are strongly modulated by the binding protein. Intramolecular hydrogen-atom transfer is suppressed in both cases. Most importantly, while there is significant singlet oxygen generation from hypericin bound to GST A1-1, binding to GST P1-1 suppresses singlet oxygen generation to almost negligible levels. The data are rationalized in terms of a simple model in which the hypericin photophysics depends entirely upon the decay of the triplet state by two competing processes, quenching by oxygen to yield singlet oxygen and ionization, the latter of these two are proposed to be modulated by A1-1 and P1-1.

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Hypericin and pseudohypericin specifically inhibit protein kinase C: Possible relation to their antiretroviral activity

Cited by 210 publications

References 15 publications

Antiproliferative Plant and Synthetic Polyphenolics Are Specific Inhibitors of Vertebrate Inositol-1,4,5-trisphosphate 3-Kinases and Inositol Polyphosphate Multikinase

Antiproliferative Plant and Synthetic Polyphenolics Are Specific Inhibitors of Vertebrate Inositol-1,4,5-trisphosphate 3-Kinases and Inositol Polyphosphate Multikinase

Reversal of NO-induced nociceptive hypersensitivity by St. John’s wort and hypericin: NF-κB, CREB and STAT1 as molecular targets

Interaction of Glutathione S-Transferase with Hypericin: A Photophysical Study

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