FLAVONOIDS BLOCK SULFATION-INDUCED CARCINOGEN ACTIVATION

说明：该项目的长期目标是增加 了解饮食成分如何影响多种 致癌过程。 假设植物中的类黄酮 食物和饮料是人磺基转移酶（ST）的有效抑制剂， 已知催化反应性硫酸酯形成的酶 许多常见的致癌物质，从而防止DNA结合，诱变和 致癌作用 目的1研究结构-活性关系 和抑制人P形成苯酚-ST（P-PST）的动力学， 脱氢表雄酮-ST（DHEA-ST）的黄酮类化合物，使用重组 酶、P-PST和DHEA-ST的模型底物和HPLC技术。 目的2 将确定最有效的黄酮类化合物对 已知人类诱变剂/致癌物的磺基缀合和生物活化，例如 熟食诱变剂N-羟基-PhIP作为P-PST的底物， 多环芳烃1-羟甲基-芘作为DHEA-ST的底物。 目的3将确定黄酮类化合物对其他人类ST的抑制作用， 包括雌激素-ST，与雌激素代谢有关， 致癌物生物活化和M-PST，与生物胺相关 代谢，都是可溶性酶。 它还将包括膜结合的 酪氨酰蛋白-ST，与翻译后修饰相关， 缩氨酸 目的4将确定最有效的抑制作用 类黄酮对P-PST，DHEA-ST和雌激素-ST在完整细胞，即人类 肝癌细胞Hep G2和人肝切片。

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.