Strategies for cancer prevention involving reduction or elimination of human exposure to environmental carcinogens may not always be possible. Inhibition of the development of cancer by the administration of chemicals may offer a practical alternative for reducing human cancer burden. However, the successful utilization of chemoprotective interventions will require solid mechanistic understanding of the action of these agents. The proposed study will investigate the mode of protective actions of dietary antioxidants (butylated hydroxytoluene, butylated hydroxyanisole and ethoxyquin) and dithiothiones, natural antioxidants found in cruciferous vegetables on aflatoxin B1 carcinogenesis. Dietary exposure of aflatoxin B1, a product of mold-related spoilage of foods, has been positively correlated with high incidences of human liver cancer in a number of underdeveloped areas of the world. This toxin is capable of covalent binding to biomolecules, especially DNA and these macromolecular adducts may pose both short and long term health risks from the resulting genotoxic lesions in people exposed to this carcinogen. Preliminary studies in our laboratories have demonstrated that a number of dietary antioxidants, including butylated hydroxytoluene, ethoxyquin and a dithiothione (oltipraz) lower the levels of DNA adduct formation by aflatoxin B1 three to seven fold when compared to control levels in rat liver following exposure in vivo. While these experiments suggest that these dietary anti-oxidants modify xenobiotic metabolizing enzymes to result in lower levels of total adduct formation, these antioxidants may also affect the kinetics of removal of these adducts from DNA in the initial 48 hours following dosage in vivo. Therefore, we specifically propose to examine the effects of dietary antioxidants on: a) the quantitative and qualitative patterns, organ specificity and repair of aflatoxin-DNA adduct formation and removal; b) the enzymological changes related to aflatoxin activation and detoxification and the kinetics of aflatoxin elimination; and c) the induction of gamma-glutamyltranspeptidase positive lesions, a short-term in vivo model for aflatoxin carcinogenesis. These studies should lead to a better understanding of antioxidant mechanisms for the inhibition of carcinogenesis and to facilitate insights into how dietary constituents may modulate the exposure status of populations to environmentally occurring carcinogens.
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