MECHANISMS OF PROTECTION AGAINST CANCER BY INDUCTION OF PHASE 2 ENZYMES

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The overall goals of this project are to lower the risk of cancer by reducing susceptibility to the toxic and neoplastic effects of carcinogens. This project exploits the well-established observation that many chemicals (some present in edible plants) protect against cancer an also induce Phase 2 detoxication enzymes such as glutathione transferases (GST) and NAD(P)H: (quinone acceptor) oxidoreductase (quinone reductase; OR), and elevate tissue glutathione levels. This cellular response boosts the capacity to dispose of carcinogens. Chemoprotective enzyme inducers are of many structural types, an are either monofunctional (elevate Phase 2 enzymes selectively), or bifunctional (elevate both Phase 1 enzymes [cytochromes P- 450] and Phase 2 enzymes [e.g., QR,GST] in animal cells and tissues. Nearly all monofunctional inducers are electrophilic. In Aim 1.1 inducer- rich edible plants will be produced in the laboratory under highly standardized conditions, and the chemistry of their inducers will be characterized. Since the isothiocyanate sulforaphane [1-isothiocyanato-4- (methylsulfinyl)butane] is the principal monofunctional inducer of some varieties of crucifers (broccoli), and blocks mammary tumor formation in rats, a major new direction is the study of the mechanism of the anticarcinogenic actions of isothiocyanates (Aim 1.2). What is the relative importance of Phase 2 enzyme induction and Phase 1 enzyme inhibition in blocking carcinogenesis, and what is the role of GSTs in isothiocyanate metabolism. Aim 1.3 is designed to evaluate, in the DMBA rat mammary tumor model, the anticarcinogenic properties of sulforaphane and synthetic analogs, of high inducer plants, and of other Phase 2 enzyme inducers that will be isolated or synthesized. Aim 1.4 is to identify the primary cellular signaling protein(s) that react with the inducers, and to elucidate the molecular mechanisms of the regulation of Phase 2 enzymes by inducers. The proposed molecular, cellular, plant and animal studies will identify new chemoprotectors, throw light on their mechanisms, and assess their efficacy in animals. They will also provide preparations of edible plants rich in inducers and suitable for human studies proposed in Project No. 2.