title: Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2.
abstract: 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.
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition-DIfE, Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558 Nuthetal, Germany.
authors.forename: Morana
authors.initials: M
authors.lastname: Bauer-Marinovic
authors.forename: Felicitas
authors.initials: F
authors.lastname: Taugner
authors.forename: Simone
authors.initials: S
authors.lastname: Florian
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D060766:Drinking Water; D005662:Furaldehyde / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D007274:Injections, Intraperitoneal; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009336:Necrosis
chemical_list: C090107:5-sulfooxymethylfurfural; D060766:Drinking Water; C008046:5-hydroxymethylfurfural; D005662:Furaldehyde; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human