It has been hypothesized that bile acids and fatty acids promote colon cancer. A proposed mechanism is a lytic effect of these surfactants on colonic epithelium, resulting in a compensatory proliferation of colonic cells. To investigate the first step of this hypothesis, we studied the lytic activity of fatty acids and physiological mixtures of fatty acids and bile acids. Experiments were performed in both erythrocytes and cultured Caco-2 cells, a model system for intestinal epithelium. Fatty acids with a chain length of 10 C atoms or more were lytic, and the hemolytic activity increased in the order C10:0 less than C18:0 less than C16:0 less than C12:0 less than C14:0 much less than C18:1 approximately C18:2 but was not dependent on their critical micellar concentration. Addition of a sublytic, submicellar concentration of cholate resulted in the formation of highly lytic mixed micelles. Lytic activity of these mixed micelles was closely associated with their micellar aggregation as determined in parallel incubations using a fluorescent micellar probe. With use of identical concentrations of fatty acids and mixed micelles, lysis of erythrocytes was highly correlated (r greater than 0.95) with lysis of Caco-2 cells measured by either release of the apical membrane-marker alkaline phosphatase or the cytosolic marker lactate dehydrogenase. This indicates that the cytolytic activity of these surfactants is not cell-type dependent. Addition of bile acids in concentrations corresponding with the total bile acid concentration in human fecal water resulted in an increased lytic activity of fatty acids.(ABSTRACT TRUNCATED AT 250 WORDS)