Description) The lipid backbones (sphingosine and ceramides) of complex sphingolipids have surfaced as highly bioactive compounds, modulating the activities of cellular protein kinases and phosphatases, and other enzymes involved in signal transduction pathways that regulate cell growth, differentiation, and transformation. For example, sphingosine reduces C3H/10T1/2 cell transformation in response to gamma irradiation and PMA, sphingosine enhances the differentiation of HL-60 cells, and sphingosine and some of its metabolites inhibit transformed cell growth and metastasis. Sphingolipids are prevalent in foods and ingested sphingolipids are hydrolyzed to sphingosine and caramide; therefore, they have the potential to be important inhibitors of carcinogenesis. To test this hypothesis, they have conducted preliminary studies of the effects of dietary sphingomyelin on the susceptibility of the colon to chemically induced cancer. In these studies, sphingomyelin was purified from milk and fed at up to 0.1 percent of the diet to mice exhibited aberrant crypts in colonic mucosa, but the number was significantly decreased in mice fed sphingomyelin. At the end of 52 weeks, mice fed sphingomyelin had a 20 percent incidence of colon tumors compared to 47 percent for the control group; therefore, it appears highly likely that dietary sphingolipids inhibit colon carcinogenesis. The goal of this application is to characterize this inhibition on a more molecular level, and to gain further insight into the digestion of sphingolipids. Crucial to this application is the applicant's ability to prepare chemically defined sphingolipids because naturally occurring sphingolipids are complex mixtures, and may have contaminants that could lead to misleading results. Therefore, they will synthesize N-palmitoyl-D-erythro-sphingosine and the corresponding sphingomyelin and analyze their digestion and fate in the GI tract of mice, as well as their inhibition of DMH-induced colon carcinogenesis. These investigators will provide fundamental information about the nutritional significance of dietary sphingolipids.
