FLAVONOIDS BLOCK SULFATION-INDUCED CARCINOGEN ACTIVATION

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DESCRIPTION: The long-term goal of this project is to increase understanding of how dietary constituents may influence the multiple processes of carcinogenesis. The hypothesis is that flavonoids in plant food and beverages are potent inhibitors of human sulfotransferases (STs), enzymes known to catalyze the formation of reactive sulfuric acid esters of many common carcinogens, thereby preventing DNA binding, mutagenesis and carcinogenesis. Aim 1 will investigate the structure-activity relationship and kinetics for inhibition of human P form phenol-ST (P-PST) and dehydroepiandrosterone-ST (DHEA-ST) by flavonoids, using recombinant enzymes, model substrates for P-PST and DHEA-ST and HPLC techniques. Aim 2 will determine the inhibitory effect of the most potent flavonoids on the sulfoconjugation and bioactivation of known human mutagens/carcinogens, e.g. the cooked-food mutagen N-hydroxy-PhIP as a substrate for P-PST and the polyaromatic hydrocarbon 1-hydroxymethyl-pyrene as a substrate for DHEA-ST. Aim 3 will determine the inhibitory effect of flavonoids on other human STs, including estrogen-ST, associated with estrogen metabolism and possibly also carcinogen bioactivation, and M-PST, associated with biogenic amine metabolism, both soluble enzymes. It will also include the membrane-bound tyrosylprotein-ST, associated with posttranslational modification of peptides. Aim 4 will determine the inhibitory effects of the most potent flavonoids on P-PST, DHEA-ST and estrogen-ST in intact cells, i.e. the human hepatoma cell Hep G2 and human liver slices.