Colon cancer is one of the two most common organ-site cancers in the world, and over 50,000 people per year die in the United States alone from this disease. This carcinoma is caused in some manner by the change in diet that results when populations become more affluent. Our high-fat, low-fiber diet is literally killing many of us. What we do not know is why. The human intestinal tract is the largest surface area of our body next to our lungs that is in constant contact with the external environment. In this case the external environment has as high a concentration of bacteria as any environment on earth. One theory on the cause of this disease is that these bacteria produce carcinogens and that the concentration of these carcinogens is highest when we consume our """"""""western"""""""" diet. We were the first to report that there was less mutagenic activity in the feces of people that consumed other types of diets; we have now identified and synthesized one of the most active mutagens in human feces, a polyene lipid, and have shown that it is produced in the colon by several Bacteroides species. This renewal proposal is to continue this work. We propose to: 1) optimize our synthesis so that sufficient amounts of pure compound can be produced for carcinogenicity tests, 2) determine which structural features of this ether-linked pentaene lipid are required to cause alterations in DNA, 3) determine the structures of any DNA adducts that are formed, 4) identify the precursor that must be present in feces for the Bacteroides to produce this mutagen, and 5) determine how to interfere with the production of this potential carcinogen in case the data show that it is a carcinogen. The possible practical human health benefits of the work are obvious, but also important is the basic information that will be gathered concerning how this new class of mutagenic compounds alter DNA and how they are formed in the colon.
