WO2004056350A1 - Utilisation d'hypericine et/ou de ses derives dans la prevention de tumeurs primaires - Google Patents

Utilisation d'hypericine et/ou de ses derives dans la prevention de tumeurs primaires Download PDF

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Publication number
WO2004056350A1
WO2004056350A1 PCT/EP2003/014853 EP0314853W WO2004056350A1 WO 2004056350 A1 WO2004056350 A1 WO 2004056350A1 EP 0314853 W EP0314853 W EP 0314853W WO 2004056350 A1 WO2004056350 A1 WO 2004056350A1
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Prior art keywords
hypericin
derivatives
prevention
john
cypiai
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PCT/EP2003/014853
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German (de)
English (en)
Inventor
Ivar Roots
Dieter Schwarz
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Charite-Universitäts Medizin Berlin (Charite)
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Priority to AU2003298237A priority Critical patent/AU2003298237A1/en
Priority to EP03795961A priority patent/EP1583521A1/fr
Publication of WO2004056350A1 publication Critical patent/WO2004056350A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/38—Clusiaceae, Hypericaceae or Guttiferae (Hypericum or Mangosteen family), e.g. common St. Johnswort
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants

Definitions

  • the present invention relates to the use of hypericin and / or its derivatives for the manufacture of a medicament for the prevention of primary tumors.
  • the invention also relates to the use of hypericin and / or its derivatives for the production of a functional food or food supplement for tumor prevention and the food or food supplement comprising hypericin in a nutritionally effective amount.
  • Hypericin can preferably be used in the form of a hypericin-rich vegetable dry extract, preferably from St. John's wort.
  • Drug compositions contain enormous potential for life improvement. It is known that, for example, polycyclic aromatic hydrocarbons (PAHs) are disease-triggering substances. PAHs can be ingested from the environment (exhaust gases) or when smoking, but polycyclic aromatic hydrocarbons are also formed when barbecuing. In particular, they are held responsible for the development of mutagenic changes and malignant tumors.
  • the metabolism of these substances in the body has been the subject of numerous research work and is illustrated in FIG. 1 using the example of one of the most important representatives, benzo [a] pyrene (B [a] P). From Figure 1 it is clear that the human enzyme cytochrome P450 1A1 (CYP1A1) plays an important role in the development of the disease.
  • the first stage of bioactivation of B [a] P leads to the CYP1A1-catalyzed formation of B [a] P-7, 8-epoxide and its hydrolysis by epoxy hydrolase (EH) to B [a] P-7,8-dihydrodiol (7, 8-diol-B [a] P).
  • the resulting 7, 8-diol-B [a] P is transformed by CYP1A1 to the genotoxic ( ⁇ ) -B [a] P-r-7, t-8-dihydro-diol-t-9, 10-epoxide
  • P450 1A1 thus catalyzes both epoxidation steps in the
  • CYP1A1 is the most important enzyme involved in chemical carcinogenesis. It is induced by PAHs such as benzo [a] pyrene and activates these and many other environmental toxins and precarcinogens to the actual carcinogens (Guengerich, FP, Cancer Res. 48 (1988) 2946-2954). CYP1A1 is essentially an extrahepatic enzyme. In addition to the lungs, it is mainly found in the entire gastrointestinal tract (esophagus, stomach, thin and Large intestine), expressed in the placenta, brain and lymphocytes.
  • CYP1A1 also catalyzes the hydroxylation of B [a] P, which leads to the phenols, mainly to 3-OH-B [a] P, which are not carcinogenic products and characterize the detoxification pathway.
  • Quercetin is an important chemopreventive compound that prevents the formation of DNA adducts, as a naturally occurring flavonoid component of many fruits and vegetables, e.g. is also contained in St. John's wort.
  • Kang et al. in "Nutrition and Cancer” 35 (2) (1999), 175-179 that quercetin inhibits the formation of benzo [a] pyrene-induced DNA adducts in human Hep G2 cells by influencing the CYP1A1 gene expression.
  • quercetin can have a long-term preventive effect on the chemical cancerogenesis of people who eat foods rich in vegetables and fruits.
  • Naturally occurring plant phenols such as tannic acid, quercetin, myricetin and anthraflavonic acid are described by Das, M. et al. in "Cancer Res. 47 (3) (1987), 767-73” as potent inhibitors of PAH DNA adduct formation in the epidermis and lungs of SENCAR mice. The authors conclude that these plant-based phenols may prove suitable for modifying the risk of tumor induction by PAHs.
  • the object of the present invention was to find highly effective compounds for tumor prevention, in particular for the prevention of tumors which are caused by polycyclic aromatic hydrocarbons.
  • hypyricin and its derivatives are highly potent chemopreventive compounds for the prophylaxis of any diseases which are associated with mutagenic changes, such as e.g. neoplastic transformations, and in particular for cancer prevention.
  • Hypericin belongs to the naphthodian thrones and has the following structural formula:
  • Hypericin is a component of plants belonging to the species Hypericum (St. John's wort) [cf. A. Nahrstedt et al., Phar acopsychiat. 30 (1997) (supplement) 129-134].
  • the Pure substance hypericin can be isolated from plants or also chemically synthesized. A whole series of synthetic routes have been described (see, for example, US Pat. No. 2,707,704, EP 0 432 496). It has now been found that hypericin is a potent inhibitor of the epoxidation of 7, 8-diol-B [a] P to the diolepoxides, that is to say the terminal step leading to the ultimately genotoxic and carcinogenic products. In addition, hypericin has little or no influence on the hydroxylation of B [a] P, which leads to the phenols and is the detoxification pathway (cf. FIG. 1).
  • Hypericin is thus superior, for example, to the resveratrol described as a cancer prophylactic, which does not inhibit the hydroxylation of B [a] P, but on the other hand only slightly inhibits the epoxidation of 7, 8-diol-B [a] P to the genotoxic diols (see Fig. 2).
  • FIG. 3 shows that hypericin, on the other hand, inhibits epoxidation extremely strongly, without having any significant influence on the hydroxylation pathway, at least not at concentrations up to 5 ⁇ M, which are well above the IC 50 value of 0.5 ⁇ M for the inhibition of epoxidation lie.
  • IC 50 values were determined for hypericin and comparatively for quercetin and ⁇ -naphthoflavone.
  • the IC 50 value is the inhibitor concentration which leads to 50% inhibition of the reaction.
  • the IC 50 value of the hypericin was determined to be 0.5 ⁇ M, while, for example, that of quercetin, also a plant phenol, which has a preventive effect on chemical cancerogenesis, is 1.5 ⁇ M.
  • Even the IC 50 value of ⁇ -naphthoflavone ( ⁇ -NF, Alpha-NF), a well-known selective CYPIAI inhibitor is 0.8 ⁇ M.
  • FIG. 4 shows the reciprocal IC 50 values for hypericin, quercetin and ⁇ -naphthoflavone for comparison of the relative inhibitory potential of these substances.
  • hypericin and / or its derivatives can be used advantageously for the prevention of PAH-induced tumors, in particular for the prevention of lung carcinoma, breast carcinoma,. Portiocarcinoma, colorectal carcinoma, skin carcinoma and brain carcinoma.
  • the substances can also be used for the prevention of other diseases induced by PAHs, e.g. for the prevention of neoplastic transformations.
  • hypericin and / or its derivatives for inhibiting the epoxidation activity of the enzyme CYPIAI is also an object of the present invention.
  • pseudohypericin, protohypericin, pseudoprotohypericin, cyclopseudohypericin and emodinanthron are particularly suitable as hypericin derivatives.
  • Hypericin and its derivatives are preferably used in the form of their salts with organic or inorganic acids, e.g. as acetates or phosphates ,, used.
  • these compounds or mixtures of these compounds are formulated in a manner known per se with suitable auxiliaries and / or carriers and / or diluents to give solid or liquid dosage forms, for injection or infusion solutions or for topical dosage forms , Oral administration of the active compounds according to the invention is preferred. Parenteral administration is of course also possible.
  • the preparation of the pharmaceutical formulations is not a problem for the person skilled in the art.
  • a process for the pharmaceutical preparation of infusion or injection solutions of hypericin or hypericin derivatives is described for example in DE 39 12 433 AI.
  • Pharmaceutical formulations (especially in combination with vitamins) can using the guidelines of "Vademecum for vitamin Formulations" (2 nd ed., Ed .: Volker Buhler, Wiss. Verlagsges. Stuttgart, 2002) are manufactured.
  • hypericin-rich means that at least 0.3 to 0.35% by weight of hypericin is contained in the dry extract.
  • St. John's wort hypericin and pseudohypericin occur side by side, so hypericin-rich St. John's wort extracts next to the .
  • Hypericin always contain the pseudohypericin, which also acts in the sense of the invention.
  • the present invention also relates to a method for tumor prevention in which the pharmaceutical preparations described above are applied to the human or animal body in an amount which is sufficient and effective, the epoxidation activity of the
  • Plasma concentrations of approx. 13 ⁇ g hypericin / L which are reached in the steady state with the usual administration of 900 mg St. John's wort dry extract / day (Johne et al., In Clin. Pharmacol. Ther.
  • Hypericin derivative dose should therefore usually be about 10 to 500 ⁇ g / day, preferably 70-500 ⁇ g / day, particularly preferably from 200 to 400 ⁇ g / day.
  • the present invention furthermore relates to the use of hypericin and / or its derivatives for producing a food or nutritional supplement which promotes the breakdown of toxic and procarcinogenic substances, and the food or nutritional supplement which contains hypericin and / or its derivatives in a nutritionally effective amount , It is a functional nutritional or nutritional supplement for tumor prevention that inhibits the epoxidation activity of the enzyme CYPIAI.
  • the hypericin can preferably also be present in the form of a dry extract rich in hypericin, preferably from St. John's wort, in the food or nutritional supplement according to the invention.
  • the food or nutritional supplement according to the invention can, for example, be a food powder, it can also be pressed into tablets (swallowing and chewable tablets), filled into capsules, in liquid form or as an emulsion.
  • the food or nutritional supplement can contain milk powder, carbohydrates, vitamins, minerals, trace elements, lipids and optionally antioxidants (eg lycopene) and plant extracts.
  • the hypericin, its derivatives or the hypericin-rich extract can be added to a tried-and-tested standard vitamin formulation (eg vit. A, E, C) or prepared on the basis thereof.
  • the required daily dose can be achieved, for example, with a formulation for a tablet which contains 0.1 to 0.17 mg hypericin / hyp derivative (at a dosage of three tablets / day). If a hypericin-rich dry extract (0.3% by weight) is used, one tablet must contain at least 100 mg of the extract. It is of course possible to enrich any food or food supplement with hypericin / hypericin derivatives.
  • a simple production route can be, for example, adding a hypericin-rich St. John's wort extract.
  • the invention therefore also relates to the use of hypericin or its derivatives as an additive to known foods.
  • Figure 1 Activation of Benz [a] pyrene by CYPIAI to its ultimately carcinogenic form
  • Figure 2 Inhibition of human CYPIAI activities by resveratrol
  • Figure 3 Inhibition of human CYPIAl activities by hypericin
  • Quercetin, B [a] P, 7-ethoxyresorufin, resorufin, alpha-naphthoflavone, dilaurylphosphatidylcholine (DLPC) were purchased from SIGMA (Deisenhofen, Germany).
  • Human CYPIAI and P450 reductase were heterologously expressed in Spodoptera frugiperda (Sf9) insect cells using the baculovirus expression system and then isolated and purified.
  • the cDNAs were cloned into baculovirus transfer vectors pBlueBac4.5 (Invitrogen, Netherlands) as described by Schwarz et al. in Pharmacogenetics 10 (2000) 519-530.
  • An N-terminal 72 bp Sphl-SexAI fragment was then replaced by the same with the following modifications: the coding sequence upstream of the stop codon was expanded by a coding sequence for a thrombin cleavage site and 6xHis residues.
  • the entire modified CYPIAI sequence was then cloned into the vector pAcMP3 (Pharmingen, USA) (under the control of the 'late basic protein promoter "P CO ⁇ ) - the pAcMP3 plasmid modified in this way was amplified in E. coli and prepared recombinant baculoviruses (according to the manufacturer's protocol Pharmingen) was used.
  • the expression ' was carried out in 400 ml of Sf9 spinner cultures for about 55 h, after which the cells were harvested, lysed and the protein as CYPIAI
  • CYPIAI was electrophoretically homogeneous with a specific P450 content of 11 nmol / mg protein.
  • the expression of the reductase was carried out analogously, its purification was carried out according to the method described by Tamura et al. in Arch. Biochem. Biophys 293 (1992) 219-223.
  • This test (epoxidation of 7, 8-diol-B [a] P) serves to detect the terminal epoxidation when B [a] P is activated to give the B [a] P diol epoxides 1 and 2 (DE1 and DE2), where DE2 is the ultimate carcinogenic metabolite that leads to cancerogenesis through DNA adduct formation.
  • the 7,8-diol-B [a] P epoxidation was detected by HPLC separation and spectrophotometric detection of the products in accordance with published methodology (Yang et al., In Cancer Res. 35 (1975) 3642-3650; Schwarz et al.
  • a reconstituted enzyme system consisting of the purified enzymes (CYPIAI and P450 reductase) and lipid (DLPC).
  • the reconstituted system consisting of 200 pmol purified CYPIAI (28 nmol / ml), 900 pmol purified " reductase (56 nmol / ml) and 0.5 mg DLPC (5 mg / ml), was in 200 ul buffer (50 mM Tris / HCl , 100 mM NaCl, pH 7.5) incubated on ice for 10 min
  • 10 ⁇ l aliquots of this enzyme-lipid mix (corresponding to 10 pmol CYPIAI) per reaction with the substrate 7, 8-diol-B [a ] P (final concentration: 2 ⁇ M) and the corresponding inhibitor concentration in 200 ⁇ l buffer, then diluted to 990 ⁇ l and preincubated again for 1 min at
  • the reaction was carried out by adding 10 ⁇ l NADPH (16.6 mg / 200 ⁇ l ) was started and carried out in a water bath at 37 ° C. for 15 minutes, after which the reaction was stopped by adding 100 ⁇ l of IM K-phosphate buffer (pH 3.5) and the suspension was left for hydrolysis at 4 ° C. for 1 hour. After addition of 10 ⁇ g 1, 1 "-bi ⁇ 2-naphthol (10 ⁇ g / lO ⁇ l methanol) as an internal HPLC standard, the products and substrate were extracted twice using ethyl acetate.
  • This test (aryl hydrocarbon hydroxylation, AHH) is an assay to quantify the CYPIAI-catalyzed hydroxylation of B [a] P to 3-OH-B [a] P.
  • the reaction characterizes the detoxification path (see FIG. 1).
  • the B [a] P hydroxylation was quantified by fluorescence detection of the products according to the classic AHH test (Nebert and Gelboin in J. Biol. Chem. 243 (1968) 6242-6249).
  • the reconstituted CYPIAl system enzyme-lipid mix
  • This test (7-ethoxyresorufin-O-deethylation, EROD). is the well-known standard assay to characterize the activity of CYPIAI, which measures the conversion of the substrate to resorufin using fluorescence spectroscopy
  • the reconstituted CYPIAI system was as under example
  • the inhibition constants for hypericin and quercetin were determined by analyzing the inhibitor kinetics, ie by measuring the enzyme kinetics for different inhibitor concentrations. For hypericin, the analyzes were carried out with a substrate concentration of 2 ⁇ M for four inhibitor concentrations (0, 1, 2 and 5 ⁇ M). For quercetin, the measurements were carried out at the same substrate concentration for the following inhibitor concentrations: 0, 1, 5 and 10 ⁇ M.
  • the conversion rates were first analyzed by Lineweaver-Burk plots and the type of inhibition (competitive, non-competitive, uncompetitive or mixed type) before the kinetic constants, including the inhibition constants Ki, by non-linear regression using SIGMA-PLOT-2001 and ENZYME - KINETICS module 1.1 (software from SPSS Science Software, Erkrath, BR Germany) were determined.

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Abstract

L'invention concerne l'utilisation d'hypéricine et/ou de ses dérivés dans la production d'un médicament destiné à la prévention de tumeurs primaires. L'invention concerne également l'utilisation d'hypéricine et/ou de ses dérivés dans la production de compléments alimentaires ou d'aliments destinés à la prévention des tumeurs, ainsi que le complément alimentaire ou l'aliment comprenant de l'hypéricine dans une quantité efficace pour l'alimentation. De préférence, l'hypéricine peut se présenter sous la forme d'un extrait sec, végétal et riche en hypéricine, ledit extrait provenant de préférence du millepertuis.
PCT/EP2003/014853 2002-12-20 2003-12-19 Utilisation d'hypericine et/ou de ses derives dans la prevention de tumeurs primaires WO2004056350A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003298237A AU2003298237A1 (en) 2002-12-20 2003-12-19 Use of hypericin and/or the derivatives thereof for the prevention of primary tumours
EP03795961A EP1583521A1 (fr) 2002-12-20 2003-12-19 Utilisation d'hypericine et/ou de ses derives dans la prevention de tumeurs primaires

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10261825.9 2002-12-20
DE10261825A DE10261825A1 (de) 2002-12-20 2002-12-20 Verwendung von Hypericin und/oder dessen Derivaten zur Tumorprävention

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WO2004056350A1 true WO2004056350A1 (fr) 2004-07-08

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AU (1) AU2003298237A1 (fr)
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174542B1 (en) * 1999-07-01 2001-01-16 Pms Mood Food, Inc. Dietary supplements and food products for treating symptoms of PMS
WO2001056558A1 (fr) * 2000-01-31 2001-08-09 Yeda Research And Development Co. Ltd. Dianthraquinones polycycliques utilisees comme agents anticancereux et anti-angiogeniques
WO2001089576A2 (fr) * 2000-05-23 2001-11-29 Andreas Kubin Nouvelle preparation d'hypericine liee a des poly-n-vinylamides

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10062813A1 (de) * 2000-12-18 2002-07-11 Katharina Kern Produkt, insbesondere Nahrungsergänzungsmittel, auf der Basis von Mikroalgen

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6174542B1 (en) * 1999-07-01 2001-01-16 Pms Mood Food, Inc. Dietary supplements and food products for treating symptoms of PMS
WO2001056558A1 (fr) * 2000-01-31 2001-08-09 Yeda Research And Development Co. Ltd. Dianthraquinones polycycliques utilisees comme agents anticancereux et anti-angiogeniques
WO2001089576A2 (fr) * 2000-05-23 2001-11-29 Andreas Kubin Nouvelle preparation d'hypericine liee a des poly-n-vinylamides

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DE10261825A1 (de) 2004-07-01
AU2003298237A1 (en) 2004-07-14

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