The overall objective of the proposed research program is to provide new information that will increase our understanding of cancer causation and provide new approaches for the prevention of cancer. The proposed research is concerned with: (1) identification of proximate and ultimate mutagenic and carcinogenic metabolites of polycyclic aromatic hydrocarbons and related nitrogen- containing heterocyclic compounds in our environment. An important aim of this research is to enhance our understanding of poorly explored aspects of structure-activity relationships of diol epoxides from polycyclic aromatic hydrocarbons and nitrogen-containing heterocytes. (2) mechanisms of carcinogenesis and mutagenesis by optically active R, S, S, R bay-region diol epoxides of polycyclic aromatic hydrocarbons and nitrogen-containing heterocycles. In this research, we will use R, S, S, R bay-region diol epoxides (ultimate mutagens and carcinogens) and their closely related optically active but biologically less active or inactive S, R, R, S enantiomers from several polycyclic aromatic hydrocarbons and nitrogen-containing heterocycles as probes for identifying cellular targets that are important for mutagenesis. We will determine (a) the effect of optically active bay-region diol epoxide enantiomers on DNA base sequences in the coding region of the endogenous hypoxanthine phosphoribosyltransferase gene of Chinese hamster V-79 cells and (b) effects of optically active bay-region diol epoxide enantiomers on the fidelity of DNA polymerase (a) possible protein target for ultimate carcinogens). (3) inhibitory effects of naturally occurring dietary constituents and their derivatives on chemical carcinogenesis and ultraviolet light-induced carcinogenesis. In this research, we will attempt to identify potentially useful inhibitors of carcinogenesis and to use these inhibitors as tools for better understanding of the carcinogenic process. We will evaluate (a) potential antagonists of bay-region diol epoxides of polycyclic aromatic hydrocarbons. (b) potential inhibitory effects of curcumin, carnosol, rosemary and other dietary plant substances on chemical carcinogenesis and ultraviolet light-induced carcinogenesis and (c) potential inhibitory and/or stimulatory effects of vitamin D3, 1alpha,25-dihydroxyvitamin D3 and calcium on chemical carcinogenesis and ultraviolet light-induced carcinogenesis. Possible mechanisms of action will be evaluated.
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