Polyphenols are common constituents in botanical preparations available in over-the-counter preparations as well as in foods which are being recommended as being heart-healthy or cancer preventing. Although best known as antioxidants, their mechanisms of action also appear to include the estrogen receptor system and inhibition of protein kinases that form part of signal transduction cascades. However, the low blood concentrations of free polyphenols in blood are not consistent with their observed effects in animal models of chronic disease. This suggests that further metabolism occurs in the vicinity of the cells affected by the chronic disease, Since chronic disease is characterized by local production of oxidants, we hypothesize that the polyphenols are converted by the oxidants to novel metabolites with increased biologic activity. Specifically, we propose that polyphenols react with hypohalogenous acids (HOCl and HOBr) and with and with peroxynitrite to produce halogenated products. Using soy isoflavones as a model, we have already shown that they form mono- and dichlorinated and nitrated derivatives both in vitro and in cells induced to have respiratory bursts. The goals of this project are to determine (1) the products and rates of reaction of polyphenols with HOCl, HOBr and ONO2- using LC-MSMS and NMR; (2) the kinetics of the formation of halogenated and nitrated products of polyphenols and their physiological metabolites by inflammatory cells; (c) whether nitrated and/or halogenated polyphenols are found in tissue sites in animal models of cells; (3) whether nitrated and/or halogenated polyphenols are found in tissue sites in animal models of inflammatory disease; and (4) the effect of halogenation of polyphenols on their biochemical and biological action in model systems (cell proliferation, arterial vessel relaxation, EGF receptor autophosphorylation and estrogen receptor-dependent reporter gene expression). The polyphenols chosen for these experiments will be those that are the subject of research in the other main projects (daidzein and genistein) [Project 1], quercetin, reveratrol, and pro-anthrocyanins [Project 2] and tea polyphenols [Project 3]. In particular, the known metabolites of these polyphenols will be investigated. Polyphenols will be investigated. Polyphenols in botanical preparations developed via the activities of the Cores and the Pilot projects will also be evaluated in years 2-5.
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