Dietary isoflavone-induced, estrogen receptor-β-mediated proliferation of Caco-2 cells is modulated by gallic acid

Abstract

Dietary isoflavones and their biotransformation products (from food fermentation) are estrogen mimics which activate estrogen receptors (ER)α and ERβ. In silico molecular modelling is used to determine theoretical binding energies of genistein, daidzein and hydroxylated biotransformation products, and to investigate structure-binding energy relationships with ERβ. Results suggest that ligand hydroxyl arrangement determines binding energy and influences binding affinity. Caco-2 cells (ERβ expressing) are used to study the proliferative effect of genistein, daidzein and their hydroxylated biotransformation products. Isoflavones/biotransformation products showed weaker enhancement of Caco-2 proliferation than 17β-estradiol. The EC50s of isoflavones/biotransformation products agreed with in silico-predicted binding affinity order. Hydroxylated biotransformation products studied showed greater Caco-2 proliferative effects than the parent isoflavones except 8-hydroxygenistein, probably due to unfavourable ERβ interactions caused by 8-hydroxygenistein's extra hydroxyl. Caco-2 pre-treatment with UDP-glucose dehydrogenase inhibitor gallic acid promoted genistein/8-hydroxygenistein-mediated proliferation. This is probably due to a reduced isoflavone glucuronidation to form low estrogenicity glucuronides. Findings are discussed in the context of dietary isoflavones/gallic acid and effects on proliferation of ERβ-expressing gut cancer cells.