Sucrose, glucose and fructose have similar genotoxicity in the rat colon and affect the metabolome

Abstract

We have shown previously that a high sucrose intake increases the background level of somatic mutations and the level of bulky DNA adducts in the colon epithelium of rats. The mechanism may involve either glucose or fructose formed by hydrolysis of sucrose. Male Big Blue^® rats were fed 30% sucrose, glucose, fructose or potato starch as part of the diet. Mutation rates and bulky DNA adduct levels were determined in colon and liver. The concentration of short-chain fatty acids and pH were determined in caecum, C-peptide was determined in plasma, biomarkers for oxidative damage and proliferation were determined in colon, and a metabonomic analysis was performed in plasma and urine. The sugars increased the mutation rates in colon and the bulky adduct levels in colon and liver to a similar extent. All sugars decrease the caecal concentration of acetic acid and propionic acid. The metabonomic studies indicated disturbed amino acid metabolism and decrease in plasma and urinary acetate as a common feature for all sugars and confirmed triglyceridemic effects of fructose. In conclusion, the genotoxicity may be related to the altered chemical environment in the caecum and thereby also in the colon but we found no related changes in insulin resistance or oxidative stress.

Introduction

Colon cancer is associated with diet and other lifestyle factors typical for the Western countries, such as low intake of fruits and vegetables, sedentary lifestyle, obesity, and probably high intake of dietary energy, cooked meat, and sugar (Bruce et al., 2000, Merrill et al., 1999). Epidemiological studies show some association between colon cancer and high intake of sucrose. In a recent review 16 of 18 studies indicate that a high intake of sucrose is associated with increased risk of colon cancer (Giovannucci, 2001). In three-week exposure studies in rats sucrose increased the mutation frequency in colon (Dragsted et al., 2002, Hansen et al., 2004) and the level of bulky DNA adducts in liver and colon compared to control rats given cornstarch (Hansen et al., 2004, Moller et al., 2003). In humans, one study indicated that a high intake of sucrose may increase the proliferation rate in the colorectal epithelium, and expand the proliferative zone from less than 60% of the colonic crypt to the entire crypt (Bostick et al., 1997). Increased colon cell proliferation has also been observed in rodents, especially when sucrose is given as a bolus dose (Luceri et al., 1996). Increased cell proliferation may be a risk factor for colon cancer and it has been suggested that increased fasting insulin levels and decreased insulin sensitivity are important links between Western-type diets and colon cancer risk (Bruce et al., 2000). In a two-stage colon carcinogenesis model insulin acted as a tumour promoter when given i.v. to rats initiated with azoxymethane (Tran et al., 1996). Although sucrose is hydrolysed to the monosaccarides, fructose and glucose, shortly after ingestion, sucrose increased colon cell proliferation more than fructose and glucose in a feeding study in rats (Caderni et al., 1996). It was suggested that the increased proliferation was caused either by a rapid absorption of the fructose or glucose after ingestion of sucrose or by an increase in the insulin level caused by a rapid absorption of glucose (Caderni et al., 1996). In humans it is well known that a Western-type diet (high saturated fat and high sucrose) induces the metabolic changes associated with insulin resistance (Daly, 2003). However, insulin resistance may be caused by both fat and sucrose which are known to influence insulin sensitivity by different mechanisms (Thresher et al., 2000). The impact of intake of sucrose and fructose on markers for insulin resistance has been studied in rodents and to a lesser extent in humans. In rodents, a high intake of sucrose (>60% of total energy) or fructose (>35% of total energy), has consistently decreased insulin sensitivity, and increased fasting plasma insulin levels (Daly, 2003, Huang et al., 2004, Thresher et al., 2000), whereas glucose did not impair insulin sensitivity (Thorburn et al., 1989). In humans, the link between intake of sucrose or fructose and markers of insulin resistance is conflicting (Daly, 2003).

Other metabolic effects of simple carbohydrates have been observed. In humans, fructose is considered the most hypertriglyceridemic sugar and is thought to account for the hypertriglyceridemic effect of sucrose (Fried and Rao, 2003). Rodent feeds having high contents of sucrose and/or fructose increased the levels of triglycerides and of very low density lipoprotein (VLDL) in plasma (Farombi et al., 2004, Taghibiglou et al., 2000, Yoshino et al., 1997).

A high intake of simple sugars may also alter the colonic microenvironment, leading to changes in pH and in the formation of fermentation products such as short-chain fatty acids (SCFA), which are an important energy source for the colonic epithelium (Zambell et al., 2003). In rats, a feed with non-resistant starches or simple carbohydrates has consistently decreased caecal production of SCFA and increased pH compared to feeds rich in resistant starch (Caderni et al., 1996, Henningsson et al., 2003, Le Leu et al., 2003, Nakanishi et al., 2003).

Sugar has also been suggested to alter oxidative stress through glycoxidation processes (Miyata et al., 1997). Previous studies indicate that the genotoxicity of sucrose may not be related to oxidative DNA damage or altered DNA repair (Dragsted et al., 2002, Hansen et al., 2004, Moller et al., 2003) but increased oxidative damage may still take place in other macromolecules leading to indirect effects on DNA.

The aim of the present study was to investigate whether the colon genotoxicity of sucrose can be ascribed specifically to either fructose or glucose using Big Blue^® rats and whether the mechanisms behind this effect are related to the endogenous metabolism of the sugars, changes in colonic fermentation, colon cell turnover, colon protein oxidation or to insulin sensitivity.