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Betulae Folium) Und Phenolischer Verbindungen, Unter Besonderer Berücksichtigung Der Beeinflussung Von Metallopeptidasen

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Betulae Folium) Und Phenolischer Verbindungen, Unter Besonderer Berücksichtigung Der Beeinflussung Von Metallopeptidasen Untersuchungen zur Wirkungsweise von Birkenblättern (Betulae folium) und phenolischer Verbindungen, unter besonderer Berücksichtigung der Beeinflussung von Metallopeptidasen DISSERTATION zur Erlangung des akademischen Grades doctor rerum naturalium (Dr. rer. nat.) im Fach Pharmazie eingereicht an der Mathematisch-Naturwissenschaftlichen Fakultät I der Humboldt-Universität zu Berlin von Hedda Major, geb. Bormann geboren am 10. Februar 1972 in Berlin Präsident der Humboldt-Universität zu Berlin Prof. Dr. Jürgen Mlynek Dekan der Mathematisch-Naturwissenschaftlichen Fakultät I der Humboldt-Universität zu Berlin Prof. Dr. Bernhard Ronacher Gutachter: 1. Prof. Dr. M.F. Melzig 2. Prof. Dr. K. Hiller 3. Prof. Dr. H. Schilcher Tag der mündlichen Prüfung: 25. März 2002 Abstract Die Anwendung von Birkenblättern (Betulae folium) erfolgt zur Durchspülung der Harnwege. In der vorliegenden Arbeit wurde die Wirkungsweise der Birkenblätter auf verschiedenen Ebenen der Phytopharmakaforschung untersucht. Zunächst wurde in-vitro die Beeinflussung der Metallopeptidasen Neutrale Endopeptidase (NEP, EC 3.4.24.11), Angiotensin-Converting-Enzym (ACE, EC 3.4.15.1) und Leucin-Aminopeptidase (LAP, EC 3.4.11.2) durch Birkenblätterextrakte, -fraktionen und reine Naturstoffe untersucht. Die Auftrennung eines Methanol- und eines Ethylacetatextraktes führte nicht zur Gewinnung einzelner, für die Gesamtwirkungen der Extrakte verantwortlichen Fraktionen bzw. Komponenten. Die Eigenschaft der Flavonoide als wirksamkeitsmitbestimmende Inhaltsstoffe konnte jedoch bestätigt werden. Ein systematisches Screening von Flavonoiden ergab u.a., dass das Ausmaß der Enzymhemmung von der Anzahl der freien phenolischen OH-Funktionen bestimmt wurde und dass Flavonoidaglyka stärker die Enzyme hemmten, als die im Pflanzenmaterial vorliegenden Glykoside (IC50NEP: Myricetin 42 µmol/l, Quercetin 192 µmol/l). Die in der Birkenrinde vorkommenden Triterpene Betulinsäure und Betulinol wurden als starke Inhibitoren der LAP erkannt (IC50 7,3 ± 1,4 bzw. 8,8 ± 1,78 µmol/l). In einem nächsten Abschnitt der Arbeit wurden die Absorptionseigenschaften von Hyperosid und Rutin mit einem In- vitro-Perfusionsmodell am isolierten Rattendünndarm untersucht. Sowohl Rutin als auch Hyperosid traten unverändert als Glykoside durch den Darm in das Akzeptorkompartiment über. Auch in Form eines Birkenblätterextraktes wurde Hyperosid am Rattendünndarm absorbiert, der Extrakt veränderte jedoch nicht die Absorptionsrate. Als Mechanismus wurde der passive Transport durch die Poren der Tight junctions der Dünndarmzellen angenommen. Abschließend wurde eine Pilotstudie (n=14) durchgeführt, in der das ausgeschiedene Harnvolumen nach einmaliger Einnahme eines Birkenblättertees im Vergleich zu einer entsprechenden Menge Leitungswasser bestimmt wurde. Bei 50 % der Probanden wurde innerhalb der vierstündigen Testphase eine Zunahme der Harnproduktion beobachtet, bei den anderen 50 % stellte sich eine gegensätzliche Reaktion auf Tee und Placebo ein. Eine signifikante Erhöhung der Harnproduktion konnte somit, unter dem angegebenen Studiendesign, nicht nachgewiesen werden. Abstract Irrigation of the urinary tract is the therapeutic indication for Birch leaf (Betulae folium). In the present thesis, effects and efficacy of Birch leaves were investigated in various fields of medicinal plant research. The effects of Birch leaf extracts, their fractions, and pure natural compounds on the metallopeptidases - Neutral Endopeptidase (NEP, EC 3.4.24.11), Angiotensin Converting Enzyme (ACE, EC 3.4.15.1), and Leucine Aminopeptidase (LAP, EC 3.4.11.2) - were investigated in vitro. Phytochemical separation of extracts obtained by methanol and ethyl acetate did not result in more active fractions compared to those of the whole extracts. The ability of flavonoids to contribute to the efficacy reached by Birch leaf extracts, could be confirmed. A systematic screening could show that the inhibitory potency of flavonoids is dependent on the number of phenolic hydroxyl functions in their chemical structure. Aglycones of flavonoids were more active than their corresponding glycosides occurring in the plant material (IC50 NEP: myricetin 42 µmol/l, quercetin 192 µmol/l). Betulinic acid and betulinol, triterpenes of the bark of Betula, inhibited LAP strongly by reaching an IC50 of 7,3 ± 1,4 µmol/l and 8,8 ± 1,78 µmol/l, respectively. Furthermore, this thesis showed the absorption profiles of hyperoside and rutin in an isolated small intestine model of the rat. Both glycosides were detected in the acceptor compartment without being metabolised. Administration of hyperoside by a Birch leaf extract did not influence the absorption rate. A passive transport through the pores of the tight junctions, localized between the intestinal cells, was considered to be the mechanism of absorption of the flavonol glycosides. Finally, a human pilot study (n=14) was carried out. The excreted urinary volume was determined after a single intake of a Birch leaf infusion or tap water. An increased urine output after 4 hours of the test period was found in 50% of the volunteers. In the contrary, an opposite effect was determined in 50% of the volunteers after administration of the herbal infusion and of a placebo solution. Thus, no significant increase of urine volume could be observed under these test conditions. Birke Betula Flavonoide Hyperosid Polyphenole Betulinsäure Metallopeptidasen NEP ACE LAP Absorption Diurese Birch Betula flavonoids hyperoside polyphenols betulinic acid metallopeptidases NEP ACE LAP absorption diuresis Abkürzungsverzeichnis: αHyp Selektivität, relative Retention bzgl. Hyperosid αNar Selektivität, relative Retention bzgl. Naringin Abs Absorption ACE Angiotensin-Converting-Enzym ACN Acetonitril AMC 7-Amino-4-methylcumarin AMG Arzneimittelgesetz ANP Atriales Natriuretisches Peptid BGA Bundesgesundheitsamt DAB Deutsches Arzneibuch Dammaranester 1 Dammar-24-en-12-O-acetyl-3α,12β, 20(S)-trihydroxy-3- (hydrogen-propandioat) Dammaranester 2 Dammar-24-en-12-O-acetyl-3α,12β,17α,20(S)- tetrahydroxy-3-(hydrogen-propandioat) Dammaranester 3 Dammar-23(E)-en-12-O-acetyl-3α,12β,20(S),25- tetrahydroxy-3-(hydrogen-propandioat) DC Dünnschichtchromatographie DEV Droge-Extrakt-Verhältnis EC Enzyme Commission EGCG Epigallocatechingallat ESCOP European Scientific Cooperative on Phytotherapy ESI-MS Elektrospray-Ionisations-Massenspektrometrie EthacExtr. Ethylacetatextrakt Fn Resorptionsquote in % nach n-ter Probenentnahme gal Galactose HEPES N-[2-Hydroxyethyl]-piperazin-N´-[2-ethansulfonsäure] Hip-His-Leu Hippuryl-His-Leu HPLC Hochleistungs-Flüssigkeitschromatographie HWExtr. Heißwasserextrakt k.H. keine Hemmung LAP Leucin-Aminopeptidase Leu-pNA Leucin-p-Nitroanilid MeOH Methanol MeOHExtr. Extrakt aus 80%igem Methanol MS Massenspektrometrie Myr-gal Myricetin-3-galactosid n.b. nicht bestimmt NEP Neutrale Endopeptidase OPC Oligomere Proanthocyanidine Ph.Eur. Europäisches Arzneibuch (Pharmacopoea Europaea) pNA p-Nitroanilin PPC Polymere Proanthocyanidine Q-glucA Quercetin-3-glucuronid R Spannbreite (Range) RF Retentionsfaktor Rn Resorptionsrate in nmol/cm nach n-ter Probenentnahme RGG Rohglykosidgemisch rha Rhamnose rut Rutinose SAAP-AMC N-Succinyl-Ala-Ala-Phe-7-Amido-4-methylcumarin SC Säulenchromatographie SGLT-1 Natrium-Glucose-Cotransporter 1 tR Retentionszeit U unit (Enzymaktivität, U = 1 µmol/min) 1 EINLEITUNG UND ZIELSETZUNGEN 1 1.1 Überblick zu Birke und Birkenblättern (Betulae folium) 1 1.1.1 Botanik 1 1.1.2 Pharmazeutische Anwendung 1 1.2 Metallopeptidasen – Begriffsdefinition, Molekularbiologie 5 1.3 Physiologische Bedeutung der untersuchten Enzyme 6 1.3.1 NEP (EC 3.4.24.11) 7 1.3.2 ACE (EC 3.4.15.1) 8 1.3.3 LAP (EC 3.4.11.2) 10 1.4 Zielsetzungen der vorliegenden Arbeit 12 2 ERGEBNISSE 14 2.1 Effekte von Birkenblätterextrakten auf die Aktivität von Metallopeptidasen 14 2.1.1 Herstellung und phytochemische Charakterisierung der Extrakte 14 2.1.2 Beeinflussung der Enzymaktivitäten durch Extrakte 17 2.1.3 Auftrennung des methanolischen Extraktes und Beobachtung der NEP-Beeinflussung durch die hergestellten Fraktionen 19 2.1.4 Untersuchung zur wirksamsten Fraktion des methanolischen Extraktes 22 2.1.5 Gerbstoffeigenschaften von Birkenblättern und Birkenblätterextrakten 22 2.1.6 Orientierende Versuche zum Vergleich der Enzymhemmungen vor und nach Hautpulverbehandlung 23 2.1.7 Fraktionierung des Ethylacetatextraktes und Beobachtung der NEP-Beeinflussung der hergestellten Fraktionen 24 2.1.8 Testung von Extrakten anderer Pflanzen 27 2.1.8.1 Solidago virgaurea L. 28 2.1.8.2 Crataegus-sp. 29 2.1.8.3 Camellia sinensis (L.)O.Kuntze 31 2.2 Effekte von Einzelstoffen auf die Aktivität von Metallopeptidasen 32 2.2.1 Screening von Flavonoiden 32 2.2.1 Screening von Flavonoidmetaboliten 37 2.2.2 Screening von Phenylpropanderivaten, Ononin sowie Verbindungen mit mehrfacher Hydroxysubstituierung 38 2.2.3 Screening von Catechin und abgeleiteten Verbindungen 40 2.2.4 Screening von Triterpenen 42 2.2.4.1 Saponine und Sapogenine 42 2.2.4.2 Betulinsäure und Betulinol 43 2.3 Resorptionsuntersuchungen am isolierten Rattendünndarm 46 2.3.1 Vorversuche mit Flavonoiden 46 2.3.2 Qualitativer Nachweis der Flavonoide in den Akzeptormedien 47 2.3.3 Quantitative Bestimmung der absorbierten Flavonoide 49 2.4 Pilotstudie zum Wirksamkeitsnachweis von Birkenblättern 53 3 DISKUSSION 62 3.1 Fraktionierung von Birkenblätterextrakten unter Beobachtung der NEP-Beeinflussung 62 3.2 Beeinflussung von Metallopeptidasen durch Flavonoide und verwandte Verbindungen 64 3.3 Gerbstoffe in Pflanzenextrakten
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