PROMOTION BY INDOLE-3-CARBINOL AND AH RECEPTOR AGONISTS

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Indole 3-carbinol (I3C), a major constituent of cruciferous vegetables, has been shown to be an effective inhibitor of tumor initiation in a number of animal models, including trout. The potential for I3C to inhibit cancer in humans is currently under clinical trial. Potential concerns about I3C have been raised, however, by the finding (originally from our work in the trout model) that post-initiation exposure results in tumor promotion. To accurately predict efficacy and safety of I3C in humans, more knowledge about its potency and mechanism of action as a promoter are needed. In addition, it is important to understand the role of cell proliferation, oxidative stress and expression of oncogenes during promotion in the trout model. This study will address this issue by pursuing answers to the following questions: 1) How does dietary I3C shift the carcinogen dose-response curve and how does the potency of I3C as a promoter compare to its potency as an inhibitor? These studies will involve feeding 6 different levels of I3C to trout initiated with 4 different levels of aflatoxin B1; 2) Does I3C derive its promotional properties from the binding of acid condensation products to the Ah receptor? If so, the efficacy of Ah receptor binding of the various I3C derivatives should correlate with promotional potency, promotion should be subject to inhibition by Ah receptor antagonists, and sensitivity to I3C promotion should segregate with the Ah locus in congenic mice; 3) Does I3C and other promoters selectively alter the expression of cells containing different mutated p21 proteins?; 4) What are the properties of the Ah receptor in trout and what is the cellular localization of the Ah receptor in liver? Does the cellular localization of the receptor correlate with target cells for promotion and with precursors of transformed cells?; and 5) Does I3C have other mechanisms of promotion? We will examine the properties of I3C as a mitogen and compare the ability of various promoters including I3C to enhance cellular proliferation and/or oxidatively damage DNA. A knowledge of the mechanism(s) of action of I3C as a promoter are essential in order provide a foundation for predicting the risk versus benefits of this tumor modulator in humans.