title: Formation of DNA adducts in wild-type and transgenic mice expressing human sulfotransferases 1A1 and 1A2 after oral exposure to furfuryl alcohol.
abstract: Furfuryl alcohol (FFA) is present in many heat-treated foods as a result of its formation via dehydration of pentoses. It is also used legally as a flavouring agent. In an inhalation study conducted in the National Toxicology Program, FFA showed some evidence of carcinogenic activity in rats and mice. FFA was generally negative in conventional genotoxicity assays, which suggests that it may be a non-genotoxic carcinogen. However, it was recently found that FFA is mutagenic in Salmonella strains expressing appropriate sulfotransferases (SULTs), such as human or mouse SULT1A1. The same DNA adducts that were formed by FFA in these strains, mainly N (2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N (2)-MF-dG), were also detected in tissues of FFA-exposed mice and even in human lung specimens. In the present study, a single oral dose of FFA (250 mg/kg body weight) or saline was administered to FVB/N mice and transgenic mice expressing human SULT1A1/1A2 on the FVB/N background. The transgenic mice were used, since human and mouse SULT1A1 substantially differ in substrate specificity and tissue distribution. DNA adducts were studied in liver, kidney, proximal and distal small intestine as well as colon, using isotope-dilution ultra performance liquid chromatography (UPLC-MS/MS). Surprisingly, low levels of adducts that may represent N (2)-MF-dG were detected even in tissues of untreated mice. FFA exposure enhanced the adduct levels in colon and liver, but not in the remaining investigated tissues of wild-type (wt) mice. The situation was similar in transgenic mice, except that N (2)-MF-dG levels were also strongly enhanced in the proximal small intestine. These different results between wt and transgenic mice may be attributed to the fact that human SULT1A1, but not the orthologous mouse enzyme, is strongly expressed in the small intestine.
authors.affiliation: Department of Food, Water and Cosmetics, Division of Environmental Medicine, Norwegian Institute of Public Health, 0456 Oslo, Norway, Research Group Genotoxic Food Contaminants, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany, Department of Exposure and Risk Assessment, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway, Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Nuthetal, Germany Present address: Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany. anjahortemo.hoie@fhi.no.
authors.forename: Anja Hortemo
authors.initials: AH
authors.lastname: Høie
authors.affiliation: Research Group Genotoxic Food Contaminants, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany, Present address: Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany.
authors.forename: Bernhard Hans
authors.initials: BH
authors.lastname: Monien
authors.affiliation: Department of Exposure and Risk Assessment, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway.
authors.forename: Amrit Kaur
authors.initials: AK
authors.lastname: Sakhi
authors.affiliation: Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Nuthetal, Germany.
authors.forename: Hansruedi
authors.initials: H
authors.lastname: Glatt
authors.affiliation: Department of Food, Water and Cosmetics, Division of Environmental Medicine, Norwegian Institute of Public Health, 0456 Oslo, Norway, Research Group Genotoxic Food Contaminants, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany, Department of Exposure and Risk Assessment, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway, Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Nuthetal, Germany Present address: Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany.
authors.forename: Hege
authors.initials: H
authors.lastname: Hjertholm
authors.affiliation: Department of Food, Water and Cosmetics, Division of Environmental Medicine, Norwegian Institute of Public Health, 0456 Oslo, Norway, Research Group Genotoxic Food Contaminants, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, 14558 Nuthetal, Germany, Department of Exposure and Risk Assessment, Division of Environmental Medicine, Norwegian Institute of Public Health, Oslo, Norway, Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Nuthetal, Germany Present address: Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589 Berlin, Germany.
authors.forename: Trine
authors.initials: T
authors.lastname: Husøy
mesh_terms: D000818:Animals; D015239:Arylsulfotransferase / Q000235:genetics*; D002853:Chromatography, Liquid; D004247:DNA / Q000187:drug effects; D018736:DNA Adducts / Q000032:analysis*; D005663:Furans / Q000378:metabolism / Q000633:toxicity*; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D018736:DNA Adducts; D005663:Furans; D004247:DNA; C012986:furfuryl alcohol; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human; C513290:SULT1A2 protein, human