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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.

Inositol polyphosphates other than Ins(1,4,5)P3 are involved in several aspects of cell regulation. For example, recent evidence has implicated InsP6, Ins(1,3,4,5,6)P5 and their close metabolic relatives, which are amongst the more abundant intracellular inositol polyphosphates, in chromatin organization, DNA maintenance, gene transcription, nuclear mRNA transport, membrane trafficking and control of cell proliferation. However, little is known of how the intracellular concentrations of inositol polyphosphates change through the cell cycle. Here we show that the concentrations of several inositol polyphosphates fluctuate in synchrony with the cell cycle in proliferating WRK-1 cells. InsP6, Ins(1,3,4,5,6)P5 and their metabolic relatives behave similarly: concentrations are high during G1-phase, fall to much lower levels during S-phase and rise again late in the cycle. The Ins(1,2,3)P3 concentration shows especially large fluctuations, and PP-InsP5 fluctuations are also very marked. Remarkably, Ins(1,2,3)P3 turns over fastest during S-phase, when its concentration is lowest. These results establish that several fairly abundant intracellular inositol polyphosphates, for which important biological roles are emerging, display dynamic behaviour that is synchronized with cell-cycle progression.

Abstract. Anti-neutrophil cytoplasm autoantibodies (ANCA) are implicated in the pathogenesis of systemic vasculitis.