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Ginkgo biloba – bioactive ingredients
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Ginkgo biloba – bioactive ingredients

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  • 1. Lorenz Lo Sauer / 2010Flickr photos: lezumbalaberenjena, CCBYSA
  • 2.  Part 1: Introduction ◦ Gingko – the living fossil ◦ Gingko – the favorite ◦ Ingredients ◦ Egb 761 ◦ NTP studies ◦ Health benefits? / adverse effects Part 2: Primary active compounds ◦ Recapitulation: Isoprenoids ◦ Ginkgolide B MNP ◦ Flavonol ◦ Biflavones ◦ Polyprenols ◦ Alkylphenols
  • 3.  Common Names ◦ ginkgo, ginkgo biloba, fossil tree, baiguo, bai guo ye...  Own genus ◦ Ginkgophyto (pre-gymnosperm)Q: How?  Living fossil ◦ Longlived: 2.500+yrs  Tall: 20-35m (66-115ft)! Resistance to disease; insect-resistant wood,A: Tough!  aerial roots and sprouts, some fire resistance  Survivalist: „rough“ settings such as stream banks, rocky slopes, cliff edges…
  • 4.  Last decade ◦ 3000+ papers published ◦ 400+ about chemical analysis ◦ Over 3200 ginkgo-related patents filed Interests for triterpene lactones (TTLs) ◦ Ginkgolides (memory enhancers?) ◦ Bilobalide ◦ Biloba extract Ginkgo industry ◦ Revenue >1 billion $ Fig 1. Ginkgolides: structure
  • 5.  Brackets(..) list important precursors ACoA: AcylCoA terpene trilactones (Isoprenoids., IPP) (incl. AcetylCoA ) flavonol glycosides (ACoA + PP) IPP: Isopentyl pyrophosphate Biflavones (ACoA + PP) PP: pentose phosphate Proanthocyanidins (Flavonoid Synth.) AA: Aminoacids Alkylphenols (PP, Shikimpath.) simple phenolic acids (PP, Shikimpath.) 6-hydroxykynurenic acid (PP+AA) 4-O-methylpyridoxine (PP) Polyprenols (IPP)
  • 6.  (−)-Bilobalide from Ginkgo biloba leaves ≥93% (HPLC) (−)-Epicatechin ≥98% (HPLC), from green tea (−)-Epicatechin purum, ≥95.0% (HPLC) (−)-Epigallocatechin ≥95% (HPLC), from green tea (−)-Epigallocatechin analytical standard (−)-Gallocatechin ≥98% (HPLC) (−)-Riboflavin ≥98% (−)-Riboflavin BioReagent, suitable for cell culture, insect cell culture tested, ≥99% (+)-Catechin hydrate ≥98% (HPLC), powder (+)-γ-Tocopherol ≥96% (HPLC) 1-Docosanol 98% 1-Docosanol purum, ≥97.0% (GC) 1- Heptacosanol ≥98% 1-Hexacosanol ≥97% (capillary GC) 1-Hexacosanol synthetic, ≥97.0% (GC) 1-Octacosanol ≥99% (GC) 2-Isopropylphenol 98% 3,4-Dihydroxybenzoic acid purum, ≥97.0% (T) 4-Hydroxybenzoic acid ≥99% D-(−)-Fructose ≥99% D-(−)-Fructose SAJ special grade, ≥98.0% D-(+)-Xylose ≥99% D-(+)-Xylose SAJ special grade, 98.0-101.0% D-(−)-Quinic acid 98% D-(−)-Quinic acid purum, ≥98.0% (T) D-(+)-Galactose ≥99% D-(+)-Galactose BioUltra, ≥99.5% (sum of enantiomers, HPLC) D-(+)- Galactose anhydrous, cell culture tested, insect cell culture tested, powder D-(+)-Glucose ≥99.5% (GC) D-(+)-Glucose BioUltra, anhydrous, ≥99.5% (sum of enantiomers, HPLC) D-(+)-Mannose BioUltra, ≥99.5% (sum of enantiomers, HPLC) D-(+)-Mannose from wood, ≥99% D-(+)-Raffinose pentahydrate ≥98.0% D-(+)-Raffinose pentahydrate for microbiology, ≥99.0% D-(+)-Raffinose pentahydrate powder, BioReagent, suitable for cell culture D-Pantothenic acid hemicalcium salt cell culture tested, insect cell culture tested, plant cell culture tested D-Pinitol 95% L-(−)-Malic acid 95-100% (enzymatic) L-(−)-Malic acid 97%, optical purity ee: 99% (GLC) L-(−)-Malic acid SAJ special grade, ≥99.0% L-(−)-Malic acid puriss., ≥99.5% (T) L-(+)-Arabinose ≥99% L-(+)-Arabinose 98% L-(+)-Lactic acid ~98% L-Alanine ≥98% (TLC) L-Alanine ≥99.0% (NT) L- Alanine SAJ special grade, ≥99.0% L-Arginine SAJ special grade, ≥98.0% L-Arginine meets EP, USP testing specifications, BioXtra, cell culture tested, 98.5-101.0%, from non- animal source L-Arginine reagent grade, ≥98% (TLC), powder L-Ascorbic acid ≥99.0% L-Ascorbic acid 99% L-Ascorbic acid JIS special grade, ≥99.0% L-Ascorbic acid puriss. p.a., ≥99.0% (RT) L-Ascorbic acid reagent grade, crystalline, ~325 mesh L-Asparagine monohydrate ≥99% (TLC) L-Aspartic acid ≥98% L-Aspartic acid ≥99.0% (T) L-Aspartic acid SAJ special grade, ≥99.0% L-Aspartic acid reagent grade, ≥98% (TLC) L-Cysteine 97% L-Cysteine SAJ special grade, ≥98.5% L-Cysteine hydrochloride BioReagent, cell culture tested, anhydrous, from non-animal source, ≥98.0% L-Cysteine hydrochloride monohydrate JIS special grade, ≥99.0% L-Cysteine hydrochloride monohydrate from non-animal source, cell culture tested, meets EP, USP testing specifications L-Cystine ≥99.0% (T) L-Cystine SAJ special grade, ≥99.0% L-Cystine crystalline L-Glutamic acid JIS special grade, ≥99.0% L-Glutamic acid ReagentPlus®, ≥99% (TLC) L-Histidine BioUltra, ≥99.5% (NT) L-Histidine ReagentPlus®, ≥99% (TLC) L- Histidine SAJ special grade, ≥98.5% L-Histidine cell culture tested, meets EP, USP testing specifications, from non-animal source L-Homoserine L-Homoserine ≥98.0% (NT) L-Isoleucine BioUltra, ≥99.5% (NT) L-Isoleucine SAJ special grade, ≥99.0% L-Isoleucine meets EP, JP, USP testing specifications, BioXtra, cell culture tested, 98.5-101.0%, from non-animal source L-Isoleucine reagent grade, ≥98% (TLC) L-Leucine SAJ special grade, ≥99.0% L-Leucine reagent grade, ≥98% (TLC) L-Lysine ≥98% (TLC) L-Lysine SAJ special grade, ≥98.0% L-Lysine purum, crystallized, ≥98.0% (NT) L-Methionine BioXtra, meets EP, JP, USP testing specifications, cell culture tested, 99.0-101.0%, from non-animal source L-Methionine SAJ special grade, ≥98.5% L-Methionine reagent grade, ≥98% (TLC) L-Phenylalanine ≥99.0% (NT) L-Phenylalanine BioXtra, meets EP, JP, USP testing specifications, suitable for cell culture, 98.5-101.0%, from non-animal source L-Phenylalanine SAJ special grade, ≥99.0% L-Phenylalanine reagent grade, ≥98% L-Proline ≥99.0% (NT) L-Proline ReagentPlus®, ≥99% (TLC) L-Proline SAJ special grade, ≥99.0% L-Proline meets EP, USP testing specifications, cell culture tested, from non-animal source L-Serine ≥99.0% (NT) L-Serine ReagentPlus®, ≥99% (TLC) L-Threonine BioXtra, cell culture tested, meets EP, JP, USP testing specifications, from non- animal source, 99.0-101.0% L-Threonine reagent grade, ≥98% (TLC) L-Tryptophan BioUltra, ≥99.5% (NT) L-Tryptophan meets EP, JP, USP testing specifications, BioXtra, cell culture tested, ≥99.0%, from non-animal source L-Tryptophan reagent grade, ≥98% (TLC) L-Tyrosine BioXtra, cell culture tested, meets EP, USP testing specifications, ≥99.0%, from non-animal source L-Tyrosine SAJ special grade, ≥99.0% L-Valine SAJ special grade, ≥98.5% L-Valine meets EP, JP, USP testing specifications, cell culture tested, 98.5-101.0%, from non-animal source L-Valine reagent grade, ≥98% (TLC) Acacetin ≥97.0% (HPLC) Acenaphthene 99% Acetic acid ≥99.7% Acetic acid ≥99.7% Acetic acid ≥99.7%, SAJ super special grade Acetic acid 99.5-100.0% Acetic acid JIS special grade, ≥99.7% Acetic acid ReagentPlus®, ≥99% Acetic acid SAJ first grade, ≥99.0% Acetic acid purum, ≥99.0% (T) Amentoflavone ≥99.0% (HPLC) Apigenin ≥95.0% (HPLC) Apigenin 95% Apigenin ~95% (TLC), from parsley, powder Arachidic acid ≥99% Arachidic acid puriss., synthetic, ≥99.0% (GC) Behenic acid 99% Behenic acid puriss., ≥99.0% (GC) Benzoic acid ReagentPlus®, 99% Benzoic acid SAJ first grade, ≥99.5% Benzoic acid SAJ special grade, ≥99.5% Benzoic acid purum, ≥99.0% (T) Butyric acid ≥99% Butyric acid SAJ special grade, ≥99.5% Campesterol ~65%, crystalline Choline chloride BioReagent, suitable for cell culture, suitable for insect cell culture, ≥98%, powder Citric acid ≥99% Citric acid 99% Citric acid BioUltra, anhydrous, ≥99.5% (T) Citric acid SAJ first grade, ≥99.5% Citric acid cell culture tested, anhydrous Dodecanoic acid ≥99% (GC/titration) Ergosterol ≥95.0% (HPLC) Formic acid JIS special grade, ≥98.0% Formic acid SAJ first grade, 88.0-89.5% Formic acid puriss. p.a., ~98% (T) Formic acid reagent grade, ≥95% Ginkgolide A purum, analytical standard, ≥98.0% (GC) Ginkgolide C purum, analytical standard, ≥96.0% (GC) Glycine ReagentPlus®, ≥99% (TLC) Glycine SAJ special grade, ≥99.0% Heptacosane purum, ≥98.0% (GC) Hexanoic acid ≥99.5% Hexanoic acid purum, ≥98.0% (GC) Isorhamnetin ≥95.0% (HPLC) Kaempferol ≥97.0% (HPLC) Linalool oxide purum, mixture of isomers, ≥97.0% (GC) Linoleic acid ≥99% Linolenic acid ≥99% Luteolin ≥98% (TLC), powder Myristic acid Sigma Grade, ≥99% Nicotinic acid ≥98% Nicotinic acid ≥99.5% (HPLC) Nicotinic acid SAJ special grade, ≥99.5% Nicotinic acid cell culture tested, insect cell culture tested, ~98% Nonacosane 99% Octanoic acid ≥96.0% Octanoic acid ≥98% Octanoic acid ≥99% Oleic acid ≥99% (GC) Oleic acid SAJ first grade, ≥70.0% Oleic acid suitable for cell culture, BioReagent Oxalic acid SAJ first grade, ≥97.0% Oxalic acid puriss. p.a., anhydrous, ≥99.0% (RT) Palmitic acid ≥99% Palmitic acid SAJ first grade, ≥95.0% Palmitoleic acid ≥99% (capillary GC), liquid Procyanidin B1 analytical standard Procyanidin B2 analytical standard Propionic acid 99.5% Propionic acid SAJ first grade, ≥98.0% Propionic acid insect cell culture tested, ~99% Propionic acid puriss. p.a., ≥99.5% (GC) Propionic acid reagent grade, ~99% Pyrocatechol ≥99%, powder Pyrocatechol ReagentPlus®, ≥99% Pyruvic acid 98% Quercetin 3-β-D-glucoside ≥90% (HPLC) Rutin hydrate ≥94% (HPLC), powder Rutin trihydrate purum, ≥95.0% (HPLC) Sesamin ≥95%, crystalline Shikimic acid ≥99% Sodium pyruvate ≥99%, powder, cell culture tested, insect cell culture tested Sodium pyruvate SAJ special grade, ≥95.0% Sodium succinate dibasic hexahydrate SAJ first grade, 98.0-102.0% Sodium succinate dibasic hexahydrate cell culture tested, insect cell culture tested Stearic acid CP Stearic acid Grade I, ≥98.5% (capillary GC) Stearic acid SAJ first grade, ≥90.0% Stearic acid SAJ first grade, ≥90.0%, powder Stearic acid SAJ special grade, ≥95.0% Stearic acid puriss., ≥98.5% (GC) Stigmasterol ~95% Succinic acid ReagentPlus®, ≥99.0% Succinic acid SAJ first grade, ≥99.0% Succinic acid SAJ special grade, ≥99.5% Succinic acid purum p.a., ≥99.0% (T) Sucrose ≥99.5% (GC) Sucrose JIS special grade Sucrose SAJ first grade Sucrose reagent grade Tannic acid SAJ first grade Tannic acid Source: Chinese natural gall nuts (from grass) Thiamine hydrochloride BioReagent, suitable for insect cell culture, suitable for cell culture Thiamine hydrochloride SAJ special grade, ≥98.5% Thymol ≥99.5% Thymol SAJ first grade, ≥98.0% Tricosane 99% Tricosane puriss., ≥99.0% (GC) Valeric acid ≥99% Valeric acid puriss., ≥99.0% (GC) Vanillic acid 97% Vanillic acid purum, ≥97.0% (HPLC) Xanthophyll from marigold Zeaxanthin purum p.a., ≥95.0% (TLC) α-Ionone technical grade, 90% β-Carotene Type II, synthetic, ≥95% (HPLC), crystalline β-Carotene purum, ≥97.0% (UV) β-Eudesmol ≥90% (HPLC) β-Ionone 96% β-Sitosterol synthetic, ≥95% γ-Aminobutyric acid ≥99% p-Coumaric acid ≥98.0% (HPLC) p-Coumaric acid purum, ≥98.0% (HPLC) p-Cymene 99% … etcMerck
  • 7.  EGb 761: a standardized Ginkgo b. extractChemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals, T.A. van Beek, P. Montoro / J. Chromatogr. A 1216 (2009)2002–2032
  • 8.  Extract is made from Ginkgo leaves EGb 761: ◦ 5% to 7 % Terpenlactones ◦ 22% to 27 % Flavonglykosides ◦ useful subst. (Ginkgolides, Terpenlactones,…) ◦ toxic ginkgolic acid (>5ppm),... Standardized Extracts for Dementia treatment: ◦ EGb 761, LI 1370
  • 9.  traditional ◦ asthma, bronchitis, fatigue, and tinnitus recent: ◦ improve memory; treat / prevent Alzheimer’s disease ◦ Dementia ◦ decrease intermittent claudication (lame, limping, leg pain b/c o. narr. arteries); sexual dysfunction multiple sclerosis Other health conditions
  • 10.  National Toxicology Program: NTP ◦ Looked into- and carried out own studies: “NTP studies” ( http://ntp-server.niehs.nih.gov/ ) best researched ◦ dementia, memory impairment, intermittent claudication, tinnitus Egb 761 ineffective vs ◦ Dementia, Alzheimers ◦ slowing cognitive decline ◦ lowering blood pressure ◦ reducing hypertension NTP Flyer (June/2010) ◦ No clear benefits of Egb 761 thus far! ◦ www.niehs.nih.gov/health/assets/docs_f_o/ntp_gingko.pdf
  • 11.  headache, nausea, gastrointestinal upset, diarrhea, dizziness, and/or allergic skin reactions ◦ occasionally severe allergic reactions Potentiates anticoagulants (slide 14) Fresh (raw) ginkgo seeds contain ginkgotoxin ◦ Discarded in Egb 761
  • 12.  Flavonoids (- glycosides)  terpenoids (ginkgolide, bilobalide)  14C markers in Ginkgolide =terpenoid origin(polycyclic Hydroxylactone) Fig 2. Structural formulas of ginkgolides and biolbalideChemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals, T.A. van Beek, P. Montoro / J. Chromatogr. A 1216 (2009)2002–2032
  • 13. Color Atlas of Biochemistry, 3rd Edition, Jan Koolman et al, Thieme 2005
  • 14.  PAF: Platelet-Activating-Factor Ginkgolide B is a strong PAF antagonist ◦ Potent & selective possible bleeding complications in accidents? Mostly in-vitro studies No drug development as of 2010 May inhibit prion neurotoxicity
  • 15.  Bleeding and Intracerebral hemorrhage  Vascular wall decreases  Potentiates Anticoagulants (e.g. Aspirin)  Definitive  PAF antagonistColor Atlas of Pharmacology, 3rd edition, Albrecht Ziegler, et al, Thieme
  • 16.  MPN short for 4- methoxypyridoxine In Ginkgo biloba Seeds Low amount in leaves Toxic Convulsant ◦ Inhibits Glutamic Acid Decarboxylase ◦ GAD decarboxylates glutamate to GABA + CO2 ID: H2O extract, IPC (C18, Fluores., [fmol]) MPN a competitive inhibitor of glutamate decarboxylase GAD and other enzymes
  • 17.  In many fruits and vegetables  Human health effects?Chemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals, T.A. van Beek, P. Montoro / J. Chromatogr. A 1216 (2009)2002–2032
  • 18.  Antifungal Lipolysis? UVB Prot.?
  • 19.  Human antitumor effects?  Present in many plants, incl. Ginkgo leaves  Sugar carriers in protein glycosylation  linearly linked 10–30 isoprene units  Common moiety: acetate, ω-units, two trans isoprene units and 10 to 20 cis-isoprene units terminal cis-isoprene unit w. ester groupChemical analysis and quality control of Ginkgo biloba leaves, extracts, and phytopharmaceuticals, T.A. van Beek, P. Montoro / J. Chromatogr. A 1216 (2009)2002–2032
  • 20.  Cytotoxic Toxicity ◦ in HET (Hen‘s egg test) studies ◦ in vivo studies Ginkgo presence ◦ Leaves 0.5%-5%, sarcotesta 5-10%, nut ~0.02% ginkgolic acids: Health effects: antitumour, antidepressant, antistressant, antiamnestic (inh. prolyl endopeptidase), antifungal, antifeedant, acaricidal, molluscicidal, insecticidal Side effects: contact allergenic, cytotoxic, embryotoxic , immunotoxic, mutagenic, probably neurotoxic!
  • 21. Wikimedia Commons, Riosnestor, 2012