FLAVONOIDS, POTENT INHIBITORS OF THE HUMAN P-FORM PHENOLSULFOTRANSFERASE - POTENTIAL ROLE IN DRUG-METABOLISM AND CHEMOPREVENTION

The common dietary constituent quercetin was a potent inhibitor of sul foconjugation of acetaminophen and minoxidil by human liver cytosol, p artially purified P-form phenolsulfotransferase (PST), and recombinant P-form PST, with IC50 values of 0.025-0.095 mu M. Quercetin inhibitio n of acetaminophen was noncompetitive with respect to acceptor substra te, with a K-i value of 0.067 mu M. A number of other flavonoids, such as fisetin, galangin, myricetin, kaempferol, chrysin, and apigenin, w ere also potent inhibitors of P-form PST-mediated sulfation, with IC50 values <1 mu M. Studies of structural analogs indicated the flavonoid 7-hydroxyl group as particularly important for potent inhibition. Pot ential human metabolites of quercetin were poor inhibitors. Curcumin, genistein, and ellagic acid (other polyphenolic natural products) were also inhibitors of P-form PST, with IC50 values of 0.38-34.8 mu M. Qu ercetin was also shown to inhibit sulfoconjugation by the human hepato ma cell line Hep G2. Although less potent in this intact cell system ( IC50 2-5 mu M), quercetin was still more potent than 2,6-dichloro-4-ni trophenol, the classical P-form PST inhibitor that has been shown to b e an inhibitor also in vivo. These observations suggest the potential for clinically important drug interactions, as well as a possible role for flavonoids as chemopreventive agents in sulfation-induced carcino genesis.