A FACTOR IN THE INCREASED RISK OF COLORECTAL-CANCER DUE TO INGESTION OF ANIMAL FAT IS INHIBITION OF COLON EPITHELIAL-CELL GLUTATHIONE-S-TRANSFERASE, AN ENZYME THAT DETOXIFIES MUTAGENS

Dietary animal fat increases the risk of colorectal cancer. A factor in the increased risk is hypothesised to result from the inhibition of isoforms of a colonic epithelial cell enzyme that detoxifies genotoxins, glutathione S-transferase, by one of the major secondary bile acids produced in the colon by fat digestion, lithocholic acid. The inhibition allows mutagens to persist in colonic epithelial cells while proliferation is stimulated by secondary bile acids, with a concomitant greater frequency of neoplasia-associated mutations than when proliferation is stimulated in the absence of the mutagens. Elements in the hypothesis include the ability of relatively low concentrations of lithocholic acid to inhibit isoforms of glutathione S-transferase found in colon epithelial cells, entry of lithocholic acid into the epithelial cells, and the correlation of neoplasia-associated colon pathology with high levels of lithocholic acid in fecal water. Higher pH values in the colonic stream are identified as exacerbating the effects of lithocholic acid by increasing its solubility. Lithocholic acid is suggested to be more inhibitory to glutathione S-transferase than the other major colonic secondary bile acid, deoxycholic acid, on the basis of inhibition-structure relationships.