Metabolism alters the chemical form of selenium (Se) and plays a key role in determining its biological activity. Our current approach is directed towards providing information of how Se metabolism could play a role in cancer prevention. There are 5 specific aims in this proposal.
Aim 1 is designed to study the in vivo metabolism of Se under conditions in which selenite and selenomethionine are found to have anticarcinogenic activities. Experiments will be carried out to quantitate 4 classes of Se metabolites: hydrogen selenide, methylselenol, dimethylselenide and trimethylselenonium. The objective is to characterize the profile of Se metabolites with respect to dose, forms of Se administered, length of exposure and other modifying factors in an attempt to determine whether the excretion of certain metabolite(s) can be correlated with the anticarcinogenic efficacy of selenite or selenomethionine treatment. The work proposed in Aim 2 is an extension of Aim 1, but advances the concept to a direct individual Se metabolism and cancer risk correlation study. Rats with different sensitivities to Se-mediated inhibition of DMBA-induced mammary carcinogenesis will be used. Animals that develop multiple tumors with a short latent period will be compared in their ability to metabolize Se with those that are tumor-free at the same time point subsequent to Se supplementation.
Aim 3 is designed to investigate the modulation of Se chemoprevention and Se metabolism by arsenic. Preliminary study from our laboratory has shown that arsenite reduced the anticarcinogenic response to selenite. A dose titration study with arsenite will be carried out in order to validate the specificity of the arsenite effect. Results of this experiment will be integrated with that from Aim 1 with the objective of cementing the hypothesis regarding the essentiality of the generation of critical Se intermediates in cancer prevention. The in vivo Se metabolism studies only measure the overall capacity of the host to handle a given load of a Se compound, but provides no information on the type and level of Se metabolites in tissues, or the extent of Se binding to cellular proteins.
Aim 4 is therefore targeted towards determination of the last two parameters in liver, kidney, muscle and the mammary gland. The results from this study will answer the question of whether tissues retain inorganic and methylated Se metabolites, and if so, how much.
Aim 5 is focused on studying the interference by Se on the activity of specific regulatory proteins. The glucocorticoid receptor is chosen here as the prototype protein model because the cysteine residues in the hormone binding domain are very sensitive to sulfhydryl modification of functional activity. Consequently the binding of Se to the -SH groups may alter ligand binding capacity or affinity. Experiments are designed to investigate the physical association of Se with the glucocorticoid receptor, the chemical form of Se involved, and the nature of the inhibition of hormone binding to the receptor. Information obtained from this project will be used to study the effect of Se on other cytoplasmic and cell membrane regulatory proteins.
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