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Naturally-occurring Phytoestrogen Precursors Are Converted to EstrogenicCompounds by Human Intestinal Bacteria            ...
METABOLISM OF SDG BY HUMAN INTESTINAL FLORA  METABOLISM OF ARCTIIN BY HUMAN  INTESTINAL FLORA                             ...
CIRCULAR DICHROISM OF (+)- AND (-)-ENTEROLACTONES MIRROR IMAGES OF (+)- AND (-)-ENTEROLACTONES  (+)-(2S,3S)-Enterolactone ...
ENANTIO SELECTIVE DEHYDROXYLATION R LENANTIO SELECTIVE OXIDATION OF DIOLS R L
DEMETHYLATION PROCEEDS IN EITHERENANTIOMER        ORAL ADMINISTRATION OF A. LAPPA         DECOCTION TO HUMAN SUBJECTSSubje...
URINARY METABOLITES OF HUMAN SUBJECTS                              AFTER ORAL ADMINISTRATION OF A. LAPPA                  ...
Time Course of Metabolite Formation after AnaerobicIncubation of Trachelogenin with Human Intestinal Bacteria             ...
Metabolic Process of Trachelogenin                          - Me                    - Me                                  ...
B/Bmax                                                                       0                                            ...
STEPWISE DEGRADATION OF PINORESINOL          Enterococcus faecalis strain PDG-1MOST OF LIGNANS ARE PRECURSORS OF ENTERODIO...
CONVERSION OF PUERARINTO EQUOL
                                                            Equol                Strain PUE...
DETECTION OF DUTERIUM-LABELED GLUCOSE              DERIVATIVE BY LC/MS                        Conclusions1.  Trachelogenin...
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  1. 1. Naturally-occurring Phytoestrogen Precursors Are Converted to EstrogenicCompounds by Human Intestinal Bacteria Masao Hattori Emeritus Professor, University of Toyama On Plant Isoflavones and LignansIn an epidemiologic study, the prevalence of breast cancerand prostate cancer was lower in Japan and Finlandcompared it with U.S.AAs a low factor of the prevalence, a Japanese soy bean andFinnish rye bread were considered as the candidates, whichcontain so called phytoestrogens, isoflavonoids and lignans.Since phytoestrogens structurally resemble estradiol, theyhave estrogenic and anti-estrogenic activities and anincidence of prostate cancer or breast cancer may decreasedepending on the blood concentrations of phytoestrogens(reverse correlation).
  2. 2. METABOLISM OF SDG BY HUMAN INTESTINAL FLORA METABOLISM OF ARCTIIN BY HUMAN INTESTINAL FLORA
  3. 3. CIRCULAR DICHROISM OF (+)- AND (-)-ENTEROLACTONES MIRROR IMAGES OF (+)- AND (-)-ENTEROLACTONES (+)-(2S,3S)-Enterolactone (-)-(2R,3R)-Enterolactone L R
  4. 4. ENANTIO SELECTIVE DEHYDROXYLATION R LENANTIO SELECTIVE OXIDATION OF DIOLS R L
  5. 5. DEMETHYLATION PROCEEDS IN EITHERENANTIOMER ORAL ADMINISTRATION OF A. LAPPA DECOCTION TO HUMAN SUBJECTSSubject: (BMI, 18.6 ± 2.1 kg/m2 22.6 ±0.4 kg/m2).Drug: (14.5 mM arctiin and 7.5 mM arctigenin)Dose: 1.0 ml/kg (= 0.5 g of /kg ) 1 -2 day 0 day 4 dayCollection of samples: Sample pretreatment: C18-Sep Pak Analysis: LC/MS/MS
  6. 6. URINARY METABOLITES OF HUMAN SUBJECTS AFTER ORAL ADMINISTRATION OF A. LAPPA DECOCTION
% of dosed arctiin and ARG e lit bo ta Me A B C D E F G H I J K L M Mean Female Male Individual Dose, 0.5 ml/kg weight Structural Similarity between Tracheloside from Safflower and Arctiin from Burdock Tracheloside Arctiin
  7. 7. Time Course of Metabolite Formation after AnaerobicIncubation of Trachelogenin with Human Intestinal Bacteria Trachelogenin 0hr 72hr 1 96hr 120hr 4 332 2 5 6 168hr 7Estimation of Trachelogenin Metabolite on the Basis of Mass Spectral Data m/z Difference Elimination Trachelogenin 388 M1 374 -14 -Me x1 M2 360 -28 -Me x2 M3 360 -28 -Me x2 M4 346 -42 -Me x3 M5 330 -58 -Me x3 -OH x1 M6 314 -74 -Me x3 -OH x2 M7 298 -90 -Me x3 -OH x3
  8. 8. Metabolic Process of Trachelogenin - Me - Me 1 2 Trachelogenin ‐Me - Me - Me 3 4 - OH - OH - OH(-)-Enterolactone, (7) 6 5 Expression of Estrogenic Action Physiological Action Co-activator Complex Estrogen CBP/p300 SRC-1 TF RNA pol ER ER mRNA Gene Products TBP ERE TATA Target Gene• Through a complex formation of estrogen receptors, estrogen, co-activators such as SCR-1, transcription of target genes isaccelerated to induce physiological actions.• Two types of estrogen receptors ERα and ERβ are reported andphytoestrogens are more strongly bound to ERβ than ERα ingeneral.
  9. 9. B/Bmax 0 10 20 30 40 50 60 -10 Arctiin Arctigenin Tracheloside Tracherogenin 1 TMB 2 3 4 5 ERα agonist (-)-Dihydroxyenterolactone 6 B/Bmax % of control (estradiol) * (-)-Enterolactone( 7) (+)-Enterolactone (-)-Enterodiol (+)-Enterodiol peroxidase B/Bmax 0 10 20 30 40 50 60 -10 Arctiin SRC-1 Arctigenin Ligand Activity against Erα Tracheloside ER Tracherogenin 1 Principle of Assay 2 Detection antibody horseradish 3 4 Erβ 5 ER β agonist (-)-Dihydroxyenterolactone 6 TMB (-)-Enterolactone( 7) * * (+)-Enterolactone (-)-Enterodiol ± SE TMB (+)-Enterodiol Oxidation product
  10. 10. STEPWISE DEGRADATION OF PINORESINOL Enterococcus faecalis strain PDG-1MOST OF LIGNANS ARE PRECURSORS OF ENTERODIOL AND ENTEROLACTONE
  11. 11. CONVERSION OF PUERARINTO EQUOL
 Equol Strain PUE Strain DZE DaidzeinJin et al.: Biol.Pharm. Bull., 31, 1621-1625 Estradiol(2008)Characterization of a Human Intestinal Bacterium that Transforms Puerarin to Daidzein Strain PUE Daidzein Puerarin Dendrograms of phylogenic affiliation of strain PUE based on 16S rRNA gene
  12. 12. DETECTION OF DUTERIUM-LABELED GLUCOSE DERIVATIVE BY LC/MS Conclusions1.  Trachelogenin was demonstrated to convert estrogenic enterolactone as well as secoisolarisiresinol diglucoside (SDG), arctiin and pinoresinol by human intestinal bacteria (HIB).   trachelogenin and arctiin to (-)-enterolactone by HIB.   ERα ERβ.4.  Dehydroxylation and oxidation of lignans by HIB were enantioselective as substrates.5.  Puerarin (C-glucosyl) was converted to estrogenic equol through daidzein by HIB.
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