Our past research has concerned the fecapentaenes which are responsible for about 90% of the mutagenicity in the feces of humans. We considered that it was imperative to determine whether these unusual compounds could be causing human colonic carcinomas. The results of our collaborations with epidemiologists and other groups now has convinced us that fecapentaenes most likely are not involved in human cancer. The most surprising findings were that there was a strong negative correlation between the amount of fecapentaenes in the feces from patients with colonic cancer compared with control patients and that the fecapentaenes are negative all animal colon carcinogenicity models. We believe that these apparent inconsistencies with the positive results in virtually all in vitro testing studies may result from a protective function of the precursors of fecapentaenes, the plasmalopentaenes, within the membranes of cells in the colonic mucosa. These polyene phospholipid precursors of the fecapentaenes may interact with reactive compounds generated at the interface of the aerobic mucosa and the anaerobic intestinal contents. We will determine the site in the human body where this family of unusual polyene plasmalogens is produced and determine whether these lipids can protect cells from certain types of genotoxins. These """"""""plasmalopentaenes"""""""" are so reactive that we must develop new methods to study their distribution in tissue. We will use new anaerobic lipid isolation techniques on both human and pig tissues and also produce monoclonal antibodies which can be used to probe tissue sections. Our working hypothesis is that these lipids are produced in the membranes covering the colonic epithelial cells so we also will test cultured colonic cells for these lipids. To accomplish certain of our goals we will have to synthesize these lipids and produce them in relatively large amounts. We will use these synthetic plasmalopentaenes in attempts to protect tissue cultured cells from the genotoxic effects of compounds which produce reactive intermediates such as peroxides, superoxide anions or singlet oxygen. If the plasmalopentaenes are mammalian membrane phospholipids with the ability to scavenge of quench toxic oxidative radicals from the colonic milieu, then they may represent the first line of cellular defense against potential carcinogens. A decrease in their concentrations then could predispose a person to colonic cancer.
