The long-term goal of this project is to elucidate the mechanisms of inhibition of carcinogenesis by tea (Camellia sinensis) and to assess its usefulness in the prevention of human cancer. Previous studies have demonstrated that tea preparations inhibit carcinogenesis in animal models and that tea polyphenols inhibit cell transformation, proliferation, and related signal transduction pathways. Plasma and tissue levels of tea polyphenols and their metabolites in animals and humans have been determined. In this project the applicant and colleagues plan to further elucidate the mechanisms of action and identify the active components involved with the following specific aims: 1. To elucidate the mechanisms of inhibition of carcinogenesis by tea in the NNK-induced lung carcinogenesis model in A/J mice and in relevant cell lines. The applicant and colleagues will study the inhibition of cell proliferation and tumor promotion by tea and tea constituents, and relate the activity to pertinent signal transduction pathways (such as MAP-kinases and AP-1 activation) in short and long term animal experiments. In-depth mechanistic studies in cell lines, on the inhibition of AP-1 and NFkB and the upstream of protein kinase cascade, will complement the animal studies and provide basic understanding of the action of tea polyphenols in general. 2. To determine the blood, urine, and tissue levels of tea polyphenols and their metabolites in rodents and humans under different experimental conditions and to understand the factors influencing these levels. Improved methods will be developed to include the analysis of many newly identified metabolites in pharmacokinetic studies. The blood and tissue levels of these compounds will serve as a reference for evaluating the mechanisms of anti-carcinogenesis and for comparing results in mice and humans. 3. To synthesize and determine the biological activities of the metabolites identified in Aim 2 in cell lines and animal models. The applicant and colleagues will address key issues concerning the bioavailability and bioactivities of O-methyl, glucuronide, and sulfate derivatives and two ring-fission metabolites of tea catechins.
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