Estrogenicity and metabolism of prenylated flavonoids and isoflavonoids

Research output: Thesisinternal PhD, WU

Abstract

 

Binding of (prenylated) flavonoids and isoflavonoids to the human estrogen receptors (hERs) might result in beneficial health effects in vivo. To understand structure-activity relationships of prenylated (iso)flavonoids towards the hERs, prenylated (iso)flavonoids were purified from extracts of licorice roots and elicited soybean seedlings. It was observed that prenylation can modulate estrogenicity. Unprenylated, chain and δ-position pyran prenylated (iso)flavonoids show an agonistic mode of action, whereas α/β-position pyran, α/β-position furan and double chain prenylated (iso)flavonoids show an antagonistic mode of action towards hERα in the yeast bioassay. The mode of estrogenic action of prenylated (iso)flavonoids could be related to structural features of the hER. In particular, the increase in length of α/β-position pyran prenylated compounds was related to indirect antagonism. It was also shown that heat and acid affected the stability of 6a-hydroxy-pterocarpans, converting them into their respective 6a,11a-pterocarpenes and consequently modulate their estrogenicity. Six prenylated isoflavonoids acted as SERMs and eight prenylated isoflavonoids showed ER subtype-selective behavior. The kind of prenylation (chain, furan or pyran) was most important for determining SERM activity, whereas additionally the backbone structure, i.e. the presence of an additional D-ring, was of importance for determining ER subtype-selectivity. To determine structure-metabolism relationships, in vitro conversion of purified prenylated (iso)flavonoids by liver enzymes was studied. These compounds can be extensively metabolized by phase I and II enzymes. A glucuronidation yield between 70-80% was observed. It was also shown that pyran and chain prenylation gave more complex hydroxylation patterns with 4 or more than 6 hydroxyl isomers, respectively, compared to unprenylated compounds (only 1 hydroxyl isomer).

 

 

 

Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • Wageningen University
Supervisors/Advisors
  • Gruppen, Harry, Promotor
  • Vincken, Jean-Paul, Co-promotor
  • Bovee, Toine, Co-promotor
Award date16 Oct 2015
Place of PublicationWageningen
Publisher
Print ISBNs9789462574748
Publication statusPublished - 2015

Keywords

  • flavonoids
  • isoflavonoids
  • glycine max
  • soyabeans
  • oestrogen receptors
  • liquorice
  • glycyrrhiza glabra
  • in vitro

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