Biological factors related to the possible genotoxicity of simple carbohydrates in the rat colon

In previous studies it has been shown that sucrose is mutagenic in the rat colon and affects the levels of bulky DNA adducts in rat liver and colon. The aim of the present work was to suggest biological factors behind these effects and discuss them in the context of sucrose as a potential cancer risk. Three papers describe the experimental studies included in this thesis. The first study was designed to test the hypothesis that sucrose enhances the colonic genotoxicity of the known food carcinogen, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ). In this study groups of 8 big blue rats were given 0 % 3.4 % or 13.4% sucrose with or without 70 ppm IQ for 21 days. Added sucrose replaced cornstarch. The mutation frequency in colon and the level of DNA adducts in colon were increased, and several markers for systemic and local oxidative damage, DNA repair, and cell proliferation in colon were determined. It was concluded that the effects of sucrose and IQ were additive and that the two substances were genotoxic by independent mechanisms. The experiment confirmed that sucrose does not affect markers of systemic or local oxidative stress. A small and statistically insignificant increase in colonic cell proliferation was observed. This might indicate an effect on insulin sensitivity. Sucrose is a disaccharide and it is cleaved to the two monosaccharides glucose and fructose shortly after ingestion. Physiological effects of sucrose intake may therefore be caused by sucrose, glucose or fructose. In the second study, groups of 12 big blue rats were given either 30 % potato starch (control), 30 % sucrose, 30 % fructose or 30 % glucose in the diet for 35 days The aim was to compare the effects of these three carbohydrates, to study their effects on markers of insulin sensitivity and to make a preliminary investigation concerning possible effects on the colon microflora. Therefore the pH of the caecum and the concentration of acetic acid, propionic acid and butyric acid (Short Chain Fatty Acids, SCFA) were also measured. The formation of bulky adducts and the colon mutation frequency was similar in magnitude in all dosed animals. The three carbohydrates seem therefore to have similar effect on colon mutation and genotoxicity. The weakly increased cell proliferation in the colon in the previous experiment might indicate an effect on insulin sensitivity. This could result in an increased insulin secretion, which is known to increase cell proliferation. A marker for mean insulin plasma concentration (C-peptide) was therefore included. This time we observed no indication of an increased cell proliferation seen in the previous experiment and also C-peptide was unchanged. We conclude therefore that insulin resistance does not seem to be involved in the rat colon mutagenesis caused by the sugars. The three sugars decreased the concentration of acetic acid and propionic acid, whereas no effect was observed on the concentration of butyric acid. As acetic acid and propionic acid are important elements in the synthesis of the cell membrane, and in the supply of energy to the colon cells a decrease in the level of these substances may affect the function of the cell and the epithelial cell membrane making the cell more prone to damage. To investigate possible systemic effects on metabolism a metabonomic study on plasma and urine was also performed. This lead to the conclusion that acetate concentrations were also decreased systemically. The metabonomic part of this study also indicates that glucose and fructose affect lipoprotein metabolism differently, but this difference seems unrelated to their genotoxic actions in colon. The changes in caecal pH and in the caecal concentration of acetic acid and propionic acid in the second experiment indicate that intake of simple carbohydrates may negatively affect the colonic microflora. This is opposite to the well-known effects of resistant starches and of fibres such as inulins and oligofructoses. In a third study, groups of 8 conventional Fischer 344 rats were given 15 % sucrose, 15 % potato starch, 15 % inulin og 15 % oligofructose. The added carbohydrates replaced cornstarch. The faecal profile of bacterial DNA and the faecal profile of bacterial RNA