SUPPRESSION OF ABERRANT COLONIC CRYPT FOCI BY SYNTHETIC SPHINGOMYELINS WITH SATURATED OR UNSATURATED SPHINGOID BASE BACKBONES

Supplementation of the diet of CF1 mice with sphingomyelin isolated fr om milk has been shown to reduce the number of aberrant crypt foci (AC F) and the appearance of colonic adenocarcinoma induced by 1,2-dimethy lhy drazine (Schmelz et al., Cancer Res 56, 4936-4941, 1996). The obje ctive of this study was to determine whether chemically synthesized sp hingomyelin reduces the appearance of ACF, one of the earliest morphol ogical changes in the development of colonic tumors, and to investigat e the specificity of this inhibition for the unsaturated sphingoid bas e backbone. 1,2-Dimethylhydrazine was administered in traperitoneally to female CF1 mice, then the animals were fed a semipurified AIN 76A d iet without supplementation (controls) or supplemented with 0.1% (wt/w t) sphingomyelin isolated from skim milk powder, synthetic N-palmitoyl sphingomyelin, or N-palmitoyldihydrosphingomyelin for four weeks. The number of ACF in the sphingomyelin-fed groups was significantly lower than in the control by 54% (p = 0.002), 52% (p = 0.002), and 70% (p < 0.0001) for milk sphingomyelin, synthetic sphingomyelin, and synthetic dihydrosphingomyelin, respectively. Suppression of ACF by the synthet ic dihydrosphingomyelin was significantly greater than by synthetic sp hingomyelin (p = 0.035). These findings establish that sphingomyelin, and not merely a possible contaminant of the naturally occurring sphin gomyelin preparation used previously, suppresses ACF formation. Furthe rmore, the greater potency of dihydrosphingomyelin reveals that the 4, 5-trans double bond of the sphingoid backbone is nor required for this suppression.