Simone L. Blagg

We investigated the ability of 37 flavonoids and flavonoid sulfoconjugates, including some abundant dietary constituents, to act as substrates and/or inhibitors of the sulfotransferase and sulfatase enzymes that interconvert active estrogens and inactive estrogen sulfates in human tissues. The enzymes studied include estrogen sulfotransferase, the thermostable phenolsulfotransferase that acts on a range of substrates including estrogens; steroid sulfatase; and two related enzymes, monoamine phenolsulfotransferase and arylsulfatase A. Several dietary flavonoids, including the soy isoflavones genistein and daidzein, were sulfated by these human sulfotransferases. Many flavonoids were potent inhibitors of thermostable phenolsulfotransferase. Genistein and equol were potent mixed inhibitors of hepatic estrogen sulfotransferase, with inhibitory constant values of 500 nM and 400 nM, respectively. Monoamine phenolsulfotransferase activity was relatively unaffected by flavonoids, but this enzyme was mainly responsible for the sulfation of flavonoids at concentrations greater than 1 micro M. Of the compounds tested, only daidzein 4,7-bisulfate, a trace metabolite in humans, significantly inhibited steroid sulfatase in the micromolar concentration range. Hence, dietary flavonoids may be able to influence the bioavailability of endogenous estrogens, and disrupt endocrine balance, by increasing the ratio of active estrogens to inactive estrogen sulfates in human tissues.

The signalling molecule DIF-1 is required for normal cell fate choice and patterning in Dictyostelium. To understand how these developmental processes are regulated will require knowledge of how cells receive and respond to the DIF-1 signal. Previously, we have described a bZIP transcription factor, DimA, which is required for cells to respond to DIF-1. However, it was unknown whether DimA activity is required to activate the DIF response pathway in certain cells or is a component of the response pathway itself. In this study, we describe the identification of a DimA-related bZIP transcription factor, DimB. Rapid changes in the subcellular localisation of both DimA and DimB in response to DIF-1 suggest that they are directly downstream of the DIF-1 signal. Genetic and biochemical interactions between DimA and DimB provides evidence that their ability to regulate diverse targets in response to DIF-1 is partly due to their ability to form homo- and heterodimeric complexes. DimA and DimB are therefore direct regulators of cellular responses to DIF-1.