Stereoselective conjugation, transport and bioactivity of s- and R-hesperetin enantiomers in vitro

W. Brand, E.F. Hoek-van den Hil, K.N. van Elk, A. Spenkelink, L.H.J. de Haan, F. Dionisi, G. Williamson, P.J. van Bladeren, I. Rietjens

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34 Citations (Scopus)


The flavanone hesperetin ((±)-4'-methoxy-3',5,7-trihydroxyflavanone) is the aglycone of hesperidin, which is the major flavonoid present in sweet oranges. Hesperetin contains a chiral C-atom and so can exist as an S- and R-enantiomer, however, in nature 2S-hesperidin and its S-hesperetin aglycone are predominant. The present study reports a chiral HPLC method to separate S- and R-hesperetin on an analytical and semipreparative scale. This allowed characterization of the stereoselective differences in metabolism and transport in the intestine and activity in a selected bioassay of the separated hesperetin enantiomers in in vitro model systems: (1) with human small intestinal fractions containing UDP-glucuronosyl transferases (UGTs) or sulfotransferases (SULTs); (2) with Caco-2 cell monolayers as a model for the intestinal transport barrier; (3) with mouse Hepa-1c1c7 cells transfected with human EpRE-controlled luciferase to test induction of EpRE-mediated gene expression. The results obtained indicate some significant differences in the metabolism and transport characteristics and bioactivity between S- and R-hesperetin, however, these differences are relatively small. This indicates that for these end points, including intestinal metabolism and transport and EpRE-mediated gene induction, experiments performed with racemic hesperetin may adequately reflect what can be expected for the naturally occurring S-enantiomer. This is an important finding since at present hesperetin is only commercially available as a racemic mixture, while it exists in nature mainly as an S-enantiomer
Original languageEnglish
Pages (from-to)6119-6125
JournalJournal of Agricultural and Food Chemistry
Issue number10
Publication statusPublished - 2010


  • mediated gene-expression
  • chiral flavonoids
  • orange juice
  • citrus
  • hesperidin
  • bioavailability
  • metabolism
  • flavanones
  • separation
  • humans

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