Colon cancer is the second most common organ-site cancer in the world. We know that this cancer is an environmental disease related to diet, particularly the diets high in fats and low in fiber - the diet of affluent populations. We do not, however, know why this correlation exists. Next to our lungs, the colon has the largest surface area of the body which is constantly exposed to the external environment - in the case of the colon, an environment consisting of as high a concentration of bacteria as found anywhere on earth. Many researchers feel that the anaerobic bacterial flora of the colon may play a significant role in the etiology of colon cancer. One theory is that these bacteria produce mutagens, carcinogens and tumor promoters that are in highest concentrations in those individuals consuming the """"""""western"""""""" diets. One class of mutagens (and potential carcinogens) found in the colon are the fecapentaenes, unique ether-linked glycerol lipids that are present in higher concentrations in the colons of people consuming western-type diets. We were the first to isolate and structurally identify these compounds; we have since synthesized them and characterized their mutagenicity and production in vitro. Fecapentaenes are produced from precursors of unknown origin by several species of Bacteroides, some of the most common bacteria in the colon. It is the presence of these precursors that appears to be responsible for why some individuals excrete (produce) these mutagens and others do not. This renewal is a continuation of our studies on the fecapentaenes and their precursors. We propose to; 1) continue our collaborations on the testing of the fecapentaenes for carcinogenic potential in animal models, 2) use selective techniques to isolate the bacteria that produce the precursors, 3) determine the structure of the precursors and synthesize them (they appear to be bacterial lipids), 4) determine the nature of DNA adducts of fecapentaene-12 and 5) study the anaerobic metabolism of fecapentaene-12 to determine whether it is metabolised to other materials which may also be mutagenic.
