5-hydroxymethylfurfural and 5-sulfooxymethylfurfural

5-Hydroxymethylfurfural (HMF) is a furanic compound produced in heat-processed foods by nonenzymatic browning reactions. HMF has been demonstrated to be hepato- and nephrotoxic in animals with a link to its metabolite 5-sulfooxymethylfurfural (SMF). To date little is known about either the formation of SMF from ingested HMF or the formation of DNA adducts in animals or human beings.. To assess SMF in vivo formation, we first performed a study in mice treated with high/low doses of oral HMF. We found increased concentrations of SMF in plasma and DNA SMF-adducts in leukocytes, hepatic tissue, and kidneys by means of LC-MS/MS, but no spatial formation in such tissues was observed by MALDI-MS imaging technology due to low sensitivity. In a second experiment, we measured the exposure to HMF in a Spanish preadolescent population. We analyzed the concentration of HMF metabolites (plasma, urine) and measured, for the first time, the presence of SMF in plasma and DNA SMF-adducts in leukocytes.. This study provides the first evidence that oral HMF is readily transformed into SMF in vivo, giving rise to the formation of DNA adducts in a direct relation with HMF intake, both in animals and human beings.

Topics: Administration, Oral; Animals; Child; DNA Adducts; Female; Food Handling; Furaldehyde; Humans; Male; Mice, Inbred Strains; Spain

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.

Topics: Animals; Arylsulfotransferase; Dose-Response Relationship, Drug; Drinking Water; Furaldehyde; Hepatocytes; Injections, Intraperitoneal; Kidney Tubules, Proximal; Liver; Mice; Mice, Inbred Strains; Mice, Transgenic; Necrosis

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.. 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.. We found no evidence for an induction of ACF by HMF or its metabolite SMF in extensive studies in mice.

Topics: Aberrant Crypt Foci; Animals; Arylsulfotransferase; Azoxymethane; Colon; Disease Models, Animal; Female; Furaldehyde; Gene Expression Regulation; Intestinal Mucosa; Kidney; Liver; Male; Mice; Mice, Inbred Strains; Mice, Transgenic

5-Hydroxymethylfurfural (HMF) is formed when sugars are acidified or heated. It is present at high levels in numerous foods. HMF is inactive in standard genotoxicity tests, but can be metabolized to a chemically reactive intermediate, 5-sulfooxymethylfurfural (SMF), which is mutagenic and carcinogenic. We recently found that direct parental administration of SMF to mice leads to abundant acute necrosis and proteinaceous casts in the proximal tubules as the dominating toxicological effect. Since proximal tubule cells actively mediate the excretion of many organic anions, we hypothesized that transporter-mediated uptake of SMF into the cells could be the reason for this selective organotoxicity. To test this hypothesis, we used human embryonic kidney (HEK293) cells stably expressing human (h) OAT1 or OAT3. SMF was a competitive inhibitor of p-aminohippurate uptake by hOAT1 and estrone sulfate uptake by hOAT3 with K(i) values of 225 microM and 1.5mM, respectively. Moreover, the initial rates of SMF uptake were 5.2- and 3.1-fold higher in cells expressing hOAT1 and hOAT3, respectively, than in control HEK293 cells. Likewise, the sensitivity of hOAT1- and hOAT3-expressing cells to SMF cytotoxicity was significantly higher than that of control cells, and was reduced by addition of probenecid, an inhibitor of OATs. Taken together, these results indicate that OAT1 and OAT3 mediate the uptake of SMF into proximal tubule cells and thereby may be involved in SMF-induced nephrotoxicity.

Topics: Cell Line; Cells, Cultured; Dose-Response Relationship, Drug; Epithelial Cells; Furaldehyde; Humans; Kidney; Kidney Tubules, Proximal; Male; Organic Anion Transport Protein 1; Organic Anion Transporters, Sodium-Independent

5-Hydroxymethylfurfural (HMF) is produced in large quantities during the processing of food containing carbohydrates and can be metabolised to 5-sulfooxymethylfurfural (SMF), a reactive intermediate that can bind to DNA and cause mutagenic effects.. Three to six days after birth, multiple intestinal neoplasia (Min/+) mice were given a single subcutaneous injection of either 500 mg/kg body weight (bw) HMF, 25 mg/kg bw SMF or vehicle (0.9 % NaCl), and were euthanised at 12 weeks of age. The number and size of adenomas and flat aberrant crypt foci (ACF) were counted in the intestine.. HMF increased the number of small intestinal adenomas (p=0.033), whereas SMF increased the flat ACF number in the large intestine (p=0.025). Treatment with HMF and SMF had no effect on the size of the adenomas.. These results show that both HMF and SMF are weak intestinal carcinogens in Min/+ mice.

Topics: Adenoma; Adenomatous Polyposis Coli Protein; Animals; Carcinogens; Female; Furaldehyde; Intestinal Neoplasms; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Necrosis; Precancerous Conditions

Heat treatment of foods containing reducing sugars and amino acids during cooking or sterilization triggers a sequence of non-enzymatic reactions collectively known as the Maillard reaction. 5-Hydroxymethylfurfural (HMF), one of the major intermediate products in the Maillard reaction, has been found to possess cytotoxic, genotoxic and tumorigenic activities, but the mechanisms of its toxic actions remain unclear. Formation of an electrophilic allylic ester bearing a good leaving group such as sulfate has been proposed as a possible metabolic activation pathway for HMF. In order to further test this possibility, we compared the mutagenic and carcinogenic activities of HMF and its chemically synthesized sulfuric acid ester, 5-sulfooxymethylfurfural (SMF). SMF induced dose-dependent increases in the number of His+ revertants in Salmonella typhimurium TA100. This intrinsic mutagenicity of SMF was significantly inhibited by ascorbic acid added to the assay media. In the presence of chloride ions, the bacterial mutagenicity of the highly polar sulfuric acid ester of HMF may also be mediated by formation of a lipophilic chloromethyl derivative. When topically applied to mouse skin, both sulfooxymethyl and chloromethyl derivatives of HMF exhibited higher skin tumor initiating activity than the parent hydroxymethyl compound. 5-Chloromethylfurfural was found to be a strong hepatocarcinogen in infant male B6C3F1 mice.

Topics: Animals; Carcinogenicity Tests; Carcinogens; Female; Furaldehyde; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred Strains; Mutagenicity Tests; Mutagens