The overall objectives of this project are to develop chemical agents that reduce the risk of human cancer. This project specifically explores a class of anticarcinogens, isothiocyanates, which are present in our diet. Many isothiocyanates potently block various carcinogens from causing tumors in various animal organs by inhibiting Phase 1 enzymes that activate carcinogens, inducing Phase 2 enzymes that detoxify activated carcinogens and inducing apoptosis that removes damaged cells, but they display a wide range of potency. Surprisingly, many isothiocyanates accumulate uphill to remarkably high concentrations in cells and the accumulation appeared to be critical for their anticarcinogen potency.
Aim 1 is designed to elucidate the molecular mechanism responsible for such rapid and concentrative cellular accumulation of isothiocyanates by relating the structure to the cellular uptake of these compounds, by determining the chemical nature of intracelluar isothiocyanates, and by identifying the critical cellular components involved in the accumulation. Since the degree of cellular accumulation of isothiocyanates is undoubtedly affected by the cellular elimination process, Aim 1 is also designed to elucidate the molecular mechanism responsible for cellular elimination of isothiocyanates by identifying the chemical form(s) which is eliminated from cells, and by identifying cellular components involved in the elimination process.
Aim 2 is designed to elucidate the effect of cellular accumulation levels of isothiocyanates on carcinogen-metabolizing enzymes, including the effect on induction of Phase 2 enzymes which detoxify carcinogens and inhibition of Phase 1 enzymes which activate carcinogens. Finally, Aim 3 is proposed to determine how cellular accumulation levels of these compounds affect their potencies in inducing apoptosis.
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