Structural requirements for stimulation of colonic cell proliferation by oxidized fatty acids

The primary autoxidation products of polyunsaturated fatty acids are known to stimulate DNA synthesis and induce ornithine decarboxylase activity in colonic mucosa. In the present study we have determined the structural features of the oxidized fatty acids necessary for the stimulation of these two components of mitogenesis. Compounds were instilled intrarectally in either aqueous or mineral oil vehicles and 3 h later (ornithine decarboxylase activity) or 12 h later (tritiated thymidine incorporation), the animals were killed and the colonic mucosa harvested for measurement of the two parameters of cell proliferation. Hydroperoxy and hydroxy fatty acids derived from oleate and stearate were studied. Ricinoleic acid and the alpha,beta-unsaturated ketone derived from oleic acid were also investigated. The minimal requirement for stimulation of cell proliferation is the presence of an oxidized functionally adjacent to a carbon-carbon double bond. All active compounds studied were roughly equipotent, which suggests a common mediator may be involved. These results imply that, in addition to biliary steroids, the autoxidation products of unsaturated fatty acids may play a role in the enhancement of tumorigenesis by high levels of dietary fat. Furthermore, the data suggest a possible mechanism of action for the active compounds.