Toxicity studies with 5-hydroxymethylfurfural and its metabolite 5-sulphooxymethylfurfural in wild-type mice and transgenic mice expressing human sulphotransferases 1A1 and 1A2
- 449 Downloads
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.
KeywordsNephrotoxicity Hepatotoxicity 5-Hydroxymethylfurfural 5-Sulphooxymethylfurfural Human sulphotransferases 1A1 and 1A2
We thank Ms. Swetlana König, Elisabeth Meyer and Elke Thom for excellent technical assistance, Dr. Gunhild Kozianowski (Südzucker AG, Mannheim, Germany) for a gift of HMF, and Drs. Albrecht Seidel and Heinz Frank (Biochemical Institute for Environmental Carcinogens, Prof. Dr. Gernot Grimmer Foundation, Grosshansdorf, Germany) for synthesizing SMF. This work has been carried out with support from the European Commission, Priority 5 on Food Quality and Safety (Contract no FOOD-CT-2003-506820 Specific Targeted Project), “Heat-generated food toxicants—identification, characterization and risk minimization”. This publication reflects the authors views and not necessarily those of the EC. The information in this document is provided as is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the information at his/her sole risk and liability.
Conflict of interest
Authors declare not having any financial or personal interest, nor having an association with any individuals or organizations that could have influenced inappropriately the submitted work.
- Bakhiya N, Monien B, Frank H, Seidel A, Glatt HR (2009) Renal organic anion transporters OAT1 and OAT3 mediate the cellular accumulation of 5-sulfooxymethylfurfural, a reactive, nephrotoxic metabolite of the Maillard product 5-hydroxymethylfurfural. Biochem Pharmacol 78:414–419PubMedCrossRefGoogle Scholar
- Dobbernack G, Meinl W, Schade N, Florian S, Wend K, Voigt I, Himmelbauer H, Gross M, Liehr T, Glatt HR (2011) Altered tissue distribution of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine DNA adducts in mice transgenic for human sulfotransferases 1A1 and 1A2. Carcinogenesis 32:1734–1740PubMedCrossRefGoogle Scholar
- Florian S, Bauer-Marinovic M, Taugner F, Dobbernack G, Monien BH, Meinl W, Glatt HR (2012) 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. Mol Nutr Food Res. doi: 10.1002/mnfr.201100574
- Glatt HR, Schneider H, Murkovic M, Monien BH, Meinl W (2012) Hydroxymethyl-substituted furans: mutagenicity in Salmonella typhimurium strains engineered for expression of various human and rodent sulphotransferases. Mutagenesis 27:41–48Google Scholar
- NTP (1999) Toxicology and carcinogenesis studies of furfuryl alcohol (CAS No.98-00-0) in F344/N rats and B6C3F1 mice (inhalation studies). Natl Toxicol Program Tech Report Ser 482:1–248Google Scholar
- NTP (2010) Toxicology and carcinogenesis studies of 5-(hydroxymethyl)-2-furfural (CAS No. 67–47-0) in F344/N rats and B6C3F1 mice (gavage studies). Natl Toxicol Program Tech Report Ser 554:1–180Google Scholar
- Romeis B (1989) Mikroskopische Technik/Romeis. München—Wien—Baltimore, Urban & SchwarzenbergGoogle Scholar
- Sommer Y (2006) 5-(Hydroxymethyl)-2-furfural: Sulfokonjugation und ihre Bedeutung für die Genotoxizität. University of Potsdam, PotsdamGoogle Scholar