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Development of new drugs based on the metabolic activation by intestinal bacteria.

Research Project

Project/Area Number 09557178
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section展開研究
Research Field Chemical pharmacy
Research InstitutionTOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY

Principal Investigator

HATTORI Masao  Toyama Medical and Pharmaceutical University, Research Institute for Wakan-Yaku, Professor, 和漢薬研究所, 教授 (40126545)

Co-Investigator(Kenkyū-buntansha) KADOTA Shigetoshi  Toyama Medical and Pharmaceutical University, Research Institute for Wakan-Yaku, Professor, 和漢薬研究所, 教授 (90115163)
SAIKI Ikuo  Toyama Medical and Pharmaceutical University, Research Institute for Wakan-Yaku, Professor, 和漢薬研究所, 教授 (80133776)
WATANABE Hiroshi  Toyama Medical and Pharmaceutical University, Research Institute for Wakan-Yaku, Professor, 和漢薬研究所, 教授 (10012642)
KOMATSU Katsuko  Toyama Medical and Pharmaceutical University, Research Institute for Wakan-Yaku, Associate Professor, 和漢薬研究所, 助教授 (50225570)
Project Period (FY) 1997 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥13,000,000 (Direct Cost: ¥13,000,000)
Fiscal Year 1999: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 1998: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1997: ¥7,200,000 (Direct Cost: ¥7,200,000)
Keywordspaeoniflorin / anti-convulsant / ginsenoside / metabolite / intestinal bacteria / Bacteroides / Peptostreptococcus / Eubacterium / アコニチン / リポアコニチン / 抗ケイレン作用 / ジンセノシド / レイン / 瀉下薬 / ペオニメタボリン / ジンセノシド Rbl / 当帰芍薬散 / 芍薬甘草湯 / 抗けいれん作用 / エピカテキン ガレート / サイコサポニン / Bifidobacterium / β-グルコシダーゼ / β-フコシダーゼ / 柴胡
Research Abstract

1. Synthesis of paeonimetabolin derivatives and their anti-convulsant activity
By incubation of paeoniflorin from peony roots with a human intestinal bacterium Lactobacillus brevis in the presence of mercapto compounds, 17 different kinds of paeonimetabolin derivatives were prepared and examined their anti-convulsant activity ; 8-(n-hexylthio)-, 8-cyclopentylthio-, 8-(p-tolylthio)-, and 8-benzoylthiopaeonimetabolin showed potent activity. After separation of the last compound by column chromatography, 7S-derivative showed the most potent anti-convulsant activity, but 7R-derivative showed the muscle relaxation effect.
2. Effects of a metabolite of ginsenoside by intestinal bacteria on metastasis and apoptosis of tumor cells
A metabolite (20S)-protopanaxadiol 20-O-glucoside of ginsenoside Rb1 showed potent anti-metastatic action in mice. As to the mechanism of the anti-metastatic action, it was demonstrated that this metabolite induced apoptosis of the tumor cells by modulating apoptosis related proteins such as cyclin D, p27 kip and c-myc etc.
3. Development of new reactions mediated by intestinal bacteria.
a. Conversion of rhein to rhein anthrone
b. Demethylation
c. Dehydroxylation
During the investigation under the above project, we islated three bacterial strains Bacteroides sp., Peptostreptococcus sp., and Eubacterium sp., from human feces, which catalyzed the new reactions a-c.

Report

(4 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • 1997 Annual Research Report
  • Research Products

    (45 results)

All Other

All Publications (45 results)

  • [Publications] Heikal O et al: "Quantitative determination of paeoniflorin and its major metabolites, paeonimetabolin I, in the rat plasma by enzyme immunoassay"J. Trad. Med.. 14. 15-19 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Isolation and identification of human intestinal bacteria capable of hydrolyzing saikosaponins"J. Trad. Med.. 14. 34-40 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takeda S. et al.: "in-vivo assessment of extrahepatic metabolism of paeoniflorin in rats : relevance to intestinal floral metabolism"J. Pharm. Pharmacol.. 49. 35-39 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Meselhy M. R. et al.: "Biotransformation of (-) epicatechin-3-O-gallate by human intestinal bacteria"Chem. Pharm. Bull.. 45. 888-893 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Heikal O et al: "Pharmacokinetic studies of paeonimetabolin I, a major metabolite of paeoniflorin from paeony roots"Biol. Pharm. Bull.. 20. 517-521 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Heikal O et al: "Effects of spacer homologous and heterologous combinations on enzyme immunoassay for paeonimetabolin I, a major metabolite of paeoniflorin"J. Trad. Med.. 14. 105-113 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Enzymes responsible for the metabolism of saikosaponins from Eubacterium sp. A-44, a human intestinal anaerobe"Biol. Pharm. Bull.. 20. 1274-1278 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "In vitro antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration"Oncology Res.. 9. 411-417 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "Effect of ginseng protopanaxatriol saponins is mediated by their intestinal bacterial metabolites after oral administration"J. Trad. Med.. 14. 180-185 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Meselhy M. R. et al.: "Disposition of Paeoniflorin and Paeonimetabolin I in Rats after Oral Administration of Toki-Shakuyaku-San (TS) and Shakuyaku-Kanzo-To (SK)"Nat. Med.. 52. 265-268 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Metabolism and Pharmacokinetics of Orally Administered Saikosaponin b1 in Conventional, Germ-Free and Eubacterium sp. A-44 Infected Gnotobiote Rats"Biol. Pharm. Bull.. 21. 588-593 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Effects of Paeoniflorin Derivatives on the Scopolamine-Induced Amnesia Using a Passive Avoidance Task in Mice ; Structure-Activity Relationship"Biol. Pharm. Bull.. 21. 1174-1179 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Potent Anticonvulsant Paeonimetabolin-I Derivatives Obtained by Incubation of Paeoniflorin and Thiol Compounds with Lactobacillus brevis"Chem. Pharm. Bull.. 46. 1486-1487 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akao T. et al.: "Intestinal Bacterial Hydrolysis is Required for the Appearance of Compound K in Rat Plasma after Oral Administration of Ginsenoside Rb1 from Panax ginseng"J. Pharm. Pharmacol.. 50. 1155-1160 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hasegawa H. et al.: "Synthesis of a biologically active fluorescent derivative of GM1, a main ginseng saponin metabolite formed by intestinal bacteria"Biol. Pharm. Bull.. 21. 513-516 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apotosis in tumor cells"Biochem. Biophys. Res. Commun.. 246. 725-730 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Anticonvulsant activity of paeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis"Biol. Pharm. Bull.. 22. 491-497 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawata Y. et al.: "Conversion of aconitine to lipoaconitine by human intestinal bacteria and their antinoceptive effects in mice"J. Trad. Med.. 16. 15-23 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Heikal O et al.: "Quantitative determination of paeoniflorin and its major metabolites, paeonimetabolin I, in the rat plasma by enzyme immunoassay."J. Trad. Med.. 14. 15-19 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Isolation and identification of human intestinal bacteria capable of hydrolyzing saikosaponins."J. Trad. Med.. 14. 34-40 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Takeda S. et al.: "In-vvo assessment of extrahepatic metabolism of paeoniflorin in rats : relevance to intestinal floral metabolism."J. Pharm. Pharmacol.. 49. 35-39 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Meselhy M. R. et al.: "Biotransformation of (-)-epicatechin-3-O-gallate by human intestinal bacteria."Chem. Pharm. Bull.. 45. 888-893 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Heikal O. A. et al.: "Pharmacokinetic studies of paeonimetabolin I, a major metabolite of paeoniflorin from paeony roots."Biol. Pharm. Bull.. 20. 517-521 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Heikal O. A. et al.: "Effects of spacer homologous and heterologous combinations on enzyme immunoassay for paeonimetabolin I, a major metabolite of paeoniflorin."J. Trad. Med.. 14. 105-113 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Enzymes responsible for the metabolism of saikosaponins from Eubacterium sp. A-44, a human intestinal anaerobe."Biol. Pharm. Bull.. 20. 1274-1278 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "In vitro antimetastatic action of ginseng protopanaxadiol saponins is based on their intestinal bacterial metabolites after oral administration."Oncology Res.. 9. 411-417 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "Effect of ginseng protopanaxatriol saponins is mediated by their intestinal bacterial metabolites after oral administration."J. Trad. Med.. 14. 180-185 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Meselhy M. R. et al.: "Disposition of Paeoniflorin and Paeonimetabolin I in Rats after Oral Administration of Toki-Shakuyaku-San (TS) and Shakuyaku-Kanzo-To (SK)."Nat. Med.. 52. 265-268 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kida H. et al.: "Metabolism and Pharmacokinetics of Orally Administered Saikosaponin b1 in Conventional, Germ-Free and Eubacterium sp.A-44 Infected Gnotobiote Rats."Biol. Pharm. Bull.. 21. 588-593 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Effects of Paeoniflorin Derivatives on the Scopolamine-Induced Amnesia Using a Passive Avoidance Task in Mice ; Structure-Activity Relationship"Biol. Pharm. Bull.. 21. 1174-1179 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Potent Anticonvulsant Paeonimetabolin-I Derivatives Obtained by Incubation of Paeoniflorin and Thiol Compounds with Lactobacillus brevis."Chem. Pharm. Bull.. 46. 1486-1487 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Akao T. et al.: "Intestinal Bacterial Hydrolysis is Required for the Appearance of Compound K in Rat Plasma after Oral Administration of Ginsenoside Rb1 from Panax ginseng."J. Pharm. Pharmacol.. 50. 1155-1160 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Hasegawa H. et al.: "Synthesis of a biologically active fluorescent derivative of GM1, a main ginseng saponin metabolite formed by intestinal bacteria."Biol. Pharm. Bull.. 21. 513-516 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Wakabayashi C. et al.: "An intestinal bacterial metabolite of ginseng protopanaxadiol saponins has the ability to induce apotosis in tumor cells."Biochem. Biophys. Res. Commun.. 246. 725-730 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Abdel-Hafez A. A. et al.: "Anticonvulsant activity of paeonimetabolin-I adducts obtained by incubation of paeoniflorin and thiol compounds with Lactobacillus brevis."Biol. Pharm. Bull.. 22. 491-497 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Kawata Y. et al.: "Conversion of aconitine to lipoaconitine by human intestinal bacteria and their antinoceptive effects in mice."J. Trad. Med.. 16. 15-23 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Atef A Abdel-Hafz 他: "Anticonvulsant Activity of Paeonimetabolin-I Adducts Obtained by Incubation of Paeoniflorin and Thiol Compounds"Biol. Pharm. Bull,. 22(5). 491-497 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Yukio Kawata 他: "Conversion of aconitine to lipoaconitine by human intestinal bacteria and their anti nociceptive effects in mice"J. Traditional Medicines. 16. 15-23 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Meselry R.Meselry他: "Disposition of paeoniflorin and paeonimetaboling in rats after oral administration of Toki-Shakuyaku-San (TS) and Shakuyaku-Kanzo-to(SK)." Natural Medicines. 52(3). 265-268 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Atef A.Abdel-Hafez他: "Effects of paeoniflorin derivatives on scopolamine-induced amnesia using a passive avoidance task in mice" Biol.Pharm.Bull.21(11). 1171-1179 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Atef A.Abdel-Hafez: "Potent anticonvalsant paeonimetabolin-I derivatives obtained by incubation of paeoniflorin and their compounds with Lactobacillus brevis" Chem.Pharm.Bull.46(9). 1486-1487 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Teruaki Akao: "Intestinal Bacterial Hydrolysis is required for the appearance of compound K in rat plasma after oral administration of ginse no side Rb_1 from Panax ginseng." J.Pharm.Pharmacol.50. 1155-1160 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Meselhy R.Meselhy: "Biotransformation of (-)epicatechin 3-O-gallate by human intestinal bacteria" Chem.Pharm.Bull.,. 45(5). 888-893 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hiroaki Kida: "Isolation and identification of human intestinal bacteria capable of hydrolyzing saikosaponins" J.Traditional Medicines. 14. 34-40 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hiroaki Kida: "Enzymes responsible for the metabolism of saikogaponins from Eubacterium sp.A-44,a human intestinal anaerobe" Biol.Pharm.Bull.,. 20(12). 1274-1278 (1997)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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