Abstract

Substantial evidence indicates that bile salts have a role in the etiology of colon cancer. The mechanism of action of bile salts, however, is largely unknown. We show here that bile salt sodium deoxycholate (NaDOC), at high physiologic individual ingests a high fat diet over severa! concentrations, induces apoptosis (programmed cell death) in a select colonic epithelial subpopulation (immature and mature goblet cells). Induction of apoptosis by NaDOC was determined using light and electron microscopy.


The colonic goblet cells of four normal human subjects showed substantial induction of apoptosis (45% to 63% of goblet cells were apoptotic) upon treatment with 1 mM NaDOC for three hours. In contrast, the normal appearing colonic mucosa from six colon cancer patients showed relatively low induction of apoptosis (only 1% to 23% of goblet cells were apoptotic) after the same treatment. Among six patients with non- malignant polyps, four resembled the cancer patients in that the frequency of apoptotic cells in the normal portion of their colon was low after NaDOC treatment (2% to 21 %); the other two had frequencies similar to that of normal individuals (61% and 63%).


These new findings suggest a novel hypothesis related to the role of bile salts in colon carcinogenesis. It is known that a high fat diet produces high levels of bile salts in the intestinal tract, and that bile salts cause DNA damage. Studies have also shown that cells with unrepaired DNA damage are subject to apoptosis. We hypothesize that when an apoptosis-resistant cells can be selected. When such a population becomes established, cells with carcinogen caused DNA damage remain viable instead of entering the apoptosis pathway. Such cells may then replicate and undergo mutation at sites of damage. These mutations may then lead to colon cancer.