Our long-term goal is to elucidate the mechanisms of inhibition of carcinogenesis by tea. As part of the Program Project, Project 2 will test the hypothesis that tea prevents carcinogenesis by inhibiting cell proliferation and enhancing apoptosis in the lung, elucidate the related mechanisms, and study the biotransformation and tissue levels of the active constituents involved with the following specific aims: 1. Elucidate the mechanisms of inhibition of carcinogenesis by tea in the NNK-induced lung carcinogenesis model in A/J mice. We will study the effect of tea on tumorigenesis, cell proliferation, apoptosis, and angiogenesis, and relate the activity to pertinent signal transduction pathways (such as MAP-kinases and AP-l) and metabolic pathways (such as arachidonic acid metabolism) in short and long term animal experiments. The effect of tea treatment on body fat levels and its relationship to carcinogenesis will be assessed. The active components for these activities will be investigated. 2. Pursue in-depth mechanistic studies in lung-derived cell lines on the inhibition of growth related signal transduction pathways by tea polyphenols in concordance with studies in Aim 1. These include fundamental studies on the cell uptake of polyphenols, inhibition of protein kinase activities related to the activation of AP-1 and NFKB, and inhibition of arachidonic acid metabolism. 3. Determine the pharmacokinetics of tea polyphenols, caffeine, and their metabolites in rodents and humans under different experimental conditions, and understand the factors influencing their levels. Improved methods will be developed to include many newly identified metabolites in pharmacokinetic studies. The plasma and tissue levels of these compounds will serve as a reference for evaluating the mechanisms of anti-carcinogenesis and for comparing results in animals and humans. 4. Determine the biological activities of the metabolites (identified in Aim 3) in cell lines and animal models. We will address key issues concerning the bioavailability and bioactivities of 0-methyl, glucuronide, and sulfate derivatives as well as ring-fission metabolites of tea catechins.
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