Many epidemiological studies provide convincing evidence for an inverse relation between the quantities of fruit and vegetables consumed and the risk of developing cancer. The Cruciferae (a vegetable family that includes broccoli, cabbage, cauliflower) play a prominent role in protection. These protective effects cannot be ascribed to a single mechanism. Nevertheless, extracts of many edible plants raise Phase 2 detoxication enzymes (e.g. glutathione transferases) in animals cells, and contain minor chemical components that are known Phase 2 enzyme inducers. Certain cultivars of Cruciferous vegetables, raised under strictly defined conditions are extremely rich in inducer activity. Large quantities of these plants will be developed in Project 1. Limited information indicates that nearly all of the inducer activity in these plants is attributable to their content of isothiocyanates an glucosinolate (biosynthetic precursors of isothiocyanates). It is the overall goal of this project to evaluate the biological properties of these plants in humans.
Aim 2. 1 is concerned with devising noninvasive methods for assessing the functional capacity of glutathione transferases (a Phase 2 enzyme) in humans. By administering test doses of an isothiocyanate (allyl isothiocyanate which can be easily and safety given in the form of horseradish), and taking advantage of the fact that isothiocyanates are rapidly and almost exclusively converted in high yield to N-acetylcysteine conjugates (dithiocarbamates) which are excreted in the urine. Glutathione transferases play a critical, and possibly rate-limiting, role in these conversions. The dithiocarbamates are easily quantitated by a cyclocondensation reaction developed for these purposes.
Aim 2. 2 seeks to answer the question to what extent glucosinolates (which are not inducers per se) are converted in the human body to isothiocyanates which are Phase 2 enzyme inducers.
In Aim 2. 3 human volunteers will be fed the aforementioned plants that are rich in inducer activity and the success of the proposed strategy will be evaluated by measuring the glutathione transferase activities, by methods developed in Aim 2.1. These experiments will provide information on whether such individuals can be expected to detoxify carcinogens and other electrophiles more rapidly and be protected against the toxic and neoplastic effects of these substances.
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