Molecular mechanisms of colon cancer chemoprevention: Studies on the potential of intestinal fermentation products to induce glutathione S-transferases in colonic epithelium cells

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Nutritional factors may enhance or prevent colorectal carcinogenesis retard the process. Some protective compounds, such as butyrate, are formed during gut flora fermentation of dietary fibre. In non-transformed cells, butyrate is utilised as an energy source. In transformed cells, it promotes apoptosis and differentiation, inhibits proliferation and induces glutathione S-transferase (GST) activity. GSTs are a superfamily of phase II enzymes that can detoxify cancer risk factors. We have shown that the genotoxic effects of 4-hydroxynonenal (HNE) a product of lipid oxidation, are decreased in cells which have been pretreated with butyrate and have increased levels of GSTP1. Preliminary findings show that GSTA4-4, which is highly specific for HNE, may also be inducible. In cells depleted of glutathione (GSH), HNE's genotoxicity is enhaced. Thus, the susceptibility of colon cells to this cancer risk factor depends on their capacity to conjugate with GSH. Consequently, nutritional intervention with highly fermentable dietary fibre could be protective by inducing GST's. Since, little is known about such mechanisms in non-transformed human colon cells, it is the aim of this proposal is to assess whether butyrate induces GST in non-tumor colon cells. Primary isolated colon cells will be treated with butyrate and the induction of GSTs and resistence forward risk factors, will be studied using a new methods of molecular biology. The results will provide first insights into as to whether this mechanism of chemoprotection could play a role in non-transformed human cells.