The roles of sulfotransferases in detoxication of many drugs, as well as in the metabolic activation of many chemical carcinogens, are increasingly recognized as highly significant. Sulfation is a key component in the metabolic formation of cytotoxic, mutagenic and/or carcinogenic molecules from xenobiotics that include benzylic alcohols derived from alkyl-substituted polycyclic aromatic hydrocarbons, hydroxylamine metabolites of aromatic amines and nitroaromatics, and allylic alcohols. The long-term goal of this research is to more fully understand and predict the roles that aryl and alcohol sulfotransferases play in the cytotoxic, mutagenic, and/or carcinogenic effects of xenobiotics that either possess or are biotransformed into metabolites containing benzylic alcohol, allylic alcohol, and N-hydroxy arylamine functional groups. The primary objective of the work proposed for the next project period is to address the gaps in our knowledge of the regulation of the catalytic function of these sulfotransferases by means other than gene expression and allelic variations. The proposed investigation is based on the central hypothesis that stereospecificity in recognition of substrates and inhibitors by aryl and alcohol sulfotransferases, the oxidative environment of these enzymes, and kinetic regulation by the co-substrate, PAPS, are critical components in the prediction of the rates of sulfation in drug metabolism and chemical carcinogenesis.
The specific aims of the research during the upcoming project period are to 1) continue elucidation of the stereoselectivity of interactions of allylic alpha-hydroxylated metabolites derived from Tamoxifen with rat STa and human SULT2A1 alcohol sulfotransferases and study the inhibition of these enzymes by Tamoxifen and its metabolites, 2) determine the role of the concentration of PAPS in the catalytic regulation of rat and human alcohol sulfotransferases, 3) determine the extent and significance of changes in kinetics resulting from disulfide bond formation in aryl and alcohol sulfotransferases, and 4) develop methods for design of isoform-specific inhibitors of aryl and alcohol sulfotransferases based on quantitative structure-activity relationships. The results of this research will provide significant new insight into the mechanisms for dynamic regulation of the catalytic function of aryl and alcohol sulfotransferases that are important to drug metabolism and chemical carcinogenesis as well as new methodology for the design of isoform-specific inhibitors of sulfotransferases. Thus, this project is highly relevant to public health due to its provision of increased understanding and prediction of the roles of sulfation both in drug metabolism and in the metabolism of xenobiotics to chemical carcinogens. Moreover, specific aim #1 has additional particular relevance to understanding and more accurately predicting the metabolism of Tamoxifen, a widely used antitumor agent and chemopreventive agent for estrogen-dependent breast cancer. ? ? ? ? ?
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