Colorectal cancer (CRC) is affected more by dietary factors than any other form of cancer. A better understanding of the mechanisms by which diet is involved in its progression may lead to strategies for its prevention. The importance of these strategies is underscored by its being the third most common neoplasia in the United States. About 6% of individuals in the U.S. will develop invasive CRC during their lifetime. Although there is little difference in incidence between sub-populations in the U.S., world-wide the CRC incidence varies some ten-fold. This wide variation adds to the concept that this cancer may be largely avoidable if causative and preventative factors are discovered. There is strong epidemiological evidence for the benefits of fruit, vegetables and fiber in CRC prevention, with much supportive data from animal studies. There is also experimental evidence indicating that various chemicals either naturally occurring or released upon processing and cooking are involved in the carcinogenesis process. However, many of the chemical compounds thought to be candidates for chemoprevention or cancer initiation and promotion have multiple effects. This is further complicated by the variability in individual genetic susceptibility and response to these dietary compounds. This project utilizes the HT29 human colon cancer cell line to investigate the role of individual dietary factors in stimulating enhanced expression of detoxification enzymes and activating enzymes involved in biotransformation of the model carcinogen benzo[a]pyrene. These studies will be in the context of the effects of dietary chemical compounds on the intracellular glutathione (GSH) redox potential and its role in the signaling process in the regulation of these biotransformation pathways. The relationship between intracellular concentrations of reduced and oxidized GSH, the expression of activator protein-1 and phosphorylation involvement in regulation of these enzymes will be investigated. This study's overall hypothesis is that the carcinogen metabolizing enzymes are influenced by measurable changes in cellular redox status affected by dietary chemical compounds.
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