Study of 5-hydroxymethylfurfural and its metabolite 5-sulfooxymethylfurfural on induction of colonic aberrant crypt foci in wild-type mice and transgenic mice expressing human sulfotransferases 1A1 and 1A2.

SCOPE: It was reported that the Maillard product 5-hydroxymethylfurfural (HMF) initiates and promotes aberrant crypt foci (ACF) in rat colon. We studied whether 5-sulfooxymethylfurfural (SMF), an electrophilic and mutagenic metabolite of HMF, is able to induce ACF in two murine models. METHODS AND RESULTS: In the first model, FVB/N mice received four intraperitoneal administrations of SMF (62.5 or 125 mg/kg) or azoxymethane (10 mg/kg). Animals were killed 4-40 weeks after the last treatment. A total of 1064 ACF and five adenocarcinomas were detected in the azoxymethane-treated groups (20 animals), but none in the negative control and SMF-treated groups (35 and 50 animals, respectively). In the second model, HMF was administered via drinking water to wild-type FVB/N mice and transgenic mice carrying several copies of human sulfotransferase (SULT) 1A1 and 1A2 genes. HMF SULT activity was clearly elevated in cytosolic fractions of colon mucosa, liver and kidney of transgenic animals compared to wild-type mice and humans. The animals (six per group) received 134 and 536 mg HMF/kg/day for 12 weeks. HMF did not induce any ACF either in wild-type or transgenic animals. CONCLUSION: We found no evidence for an induction of ACF by HMF or its metabolite SMF in extensive studies in mice.

Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2.

5-Sulphooxymethylfurfural (SMF), an electrophilic metabolite of the abundant Maillard product 5-hydroxymethylfurfural (HMF), was intraperitoneally administered to FVB/N mice. At a dosage of 250 mg/kg, most animals died after 5-11 days due to massive damage to proximal tubules. At lower dosages, administered repeatedly, tubules also were the major target of toxicity, with regeneration and atypical hyperplasia occurring at later periods. Additionally, hepatotoxic effects and serositis of peritoneal tissues were observed. SMF is a minor metabolite of HMF in conventional mice, but HMF is an excellent substrate for a major sulphotransferase (hSULT1A1) in humans. Parental FVB/N mice and FVB/N-hSULT1A1/2 mice, carrying multiple copies of the hSULT1A1/2 gene cluster, were exposed to HMF in drinking water (0, 134 and 536 mg/kg body mass/day) for 12 weeks. Nephrotoxic effects and enhanced proliferation of hepatocytes were only detected at the high dosage. They were mild and, surprisingly, unaffected by hSULT1A1/2 expression. Thus, SMF was a potent nephrotoxicant when administered as a bolus, but did not reach levels sufficient to produce serious toxicity when generated from HMF administered continuously via drinking water. This was even the case in transgenic mice expressing clearly higher HMF sulphation activity in liver and kidney than humans.

Dietary resistant starch type 3 prevents tumor induction by 1,2-dimethylhydrazine and alters proliferation, apoptosis and dedifferentiation in rat colon.

Some epidemiological and experimental studies suggest that consumption of resistant starch is preventive against colon cancer. Resistant starch leads to a fermentation-mediated increase in the formation of short-chain fatty acids, with a particularly high butyrate fraction in large bowel. Butyrate is considered to be protective against colon cancer because it causes growth arrest and apoptosis and regulates expression of proteins involved in cellular dedifferentiation in various tumor cell lines in culture. We sought to investigate these processes under conditions of a carcinogenicity experiment in vivo. In the present study, 1,2-dimethylhydrazine-treated Sprague-Dawley rats were fed standard diet (n=12) or diet with 10% hydrothermally modified Novelose 330, a resistant starch type 3 (RS3), replacing digestible starch (n=8). After 20 weeks tumor number, epithelial proliferation, apoptosis, immunoreactivity of carcinogenesis-related proteins [protein kinase C-delta (PKC-delta), heat shock protein 25 (HSP25) and gastrointestinal glutathione peroxidase (GI-GPx)], as well as mucin properties were evaluated in proximal and distal colon in situ. No tumors developed under RS3 diet, compared to a tumor incidence of 0.6+/-0.6 (P<0.05) under the standard diet. RS3 decreased the number of proliferating cells, the length of the proliferation zone and the total length of the crypt in the distal colon, but not proximal colon, and enhanced apoptosis in both colonic segments. It induced PKC-delta and HSP25 expression, but inhibited GI-GPx expression in the epithelium of distal colon. RS3 increased the number of predominantly acidic mucin containing goblet cells in the distal colon, but had no effect on the goblet cell count. We conclude that hydrothermally treated RS3 prevented colon carcinogenesis, and that this effect was mediated by enhanced apoptosis of damaged cells accompanied by changes in parameters of dedifferentiation in colonic mucosa.