Hemoglobin adducts of furfuryl alcohol in genetically modified mouse models: Role of endogenous sulfotransferases 1a1 and 1d1 and transgenic human sulfotransferases 1A1/1A2. (1st October 2018)

• Record Type: Journal Article
• Authors: Monien, Bernhard H.; Sachse, Benjamin; Meinl, Walter; Abraham, Klaus; Lampen, Alfonso; Glatt, Hansruedi
• Is Part Of: Toxicology letters. Volume 295(2018)
• Page Start: 173
• Page End: 178
• Publication Date: 2018-10-01
• Subjects: 2-SMF 2-sulfoxymethylfuran -- FFA furfuryl alcohol -- FFA-Val N-((furan-2-yl)methyl)-valine -- FFA-Val-FTH N-((furan-2-yl)methyl)-valine fluorescein thiohydantoin -- FITC fluorescein-5-isothiocyanate -- FTH fluorescein thiohydantoin -- SULT sulfotransferase -- UPLC-MS/MS ultra performance liquid chromatography-tandem mass spectrometry -- wt wild-type; Biomarker -- Furfuryl alcohol -- Protein adducts -- Edman degradation -- UPLC-MS/MS; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2018.06.008
• Languages: English
• ISSNs: 0378-4274

Abstract

Graphical abstract: Highlights: The genotoxic carcinogen furfuryl alcohol (FFA) is bioactivated by sulfo conjugation. The resulting 2-sulfoxymethylfuran forms the hemoglobin adduct FFA-Val. FFA-Val was quantified in mouse models expressing different sulfotransferases (SULT). FFA sulfo conjugation is mainly catalyzed by mouse Sult1a1 and by human SULT1A1/1A2. Levels of FFA-specific adducts in hepatic DNA and in hemoglobin correlate well. Abstract: Furfuryl alcohol (FFA) is a heat-induced food contaminant. Conversion by sulfotransferases (SULT) yields 2-sulfoxymethylfuran, which is prone to react with DNA and proteins. In order to monitor the internal FFA exposure we developed a technique for the mass spectrometric quantification of the adduct N -((furan-2-yl)methyl)-valine (FFA-Val) after cleavage from the N -termini of hemoglobin. In the current study the method was applied to investigate the influence of different SULT forms on the adduct formation in wild-type mice and three genetically modified mouse models treated with FFA. Two lines were devoid of endogenous Sult1a1 or Sult1d1, while another mouse line carried a transgene of human SULT1A1/1A2 in the Sult1a1/1d1 double knockout background. The Sult1d1 knockout did not influence adduct formation, whereas the lack of Sult1a1 reduced mean FFA-Val levels by 80% and 58% in male and female mice, respectively, in comparison to FFA-treated wild-type mice. The levels of FFA-Val in the humanized mice were elevated by factors of 2.7 (males) and 2.2 (females) as compared to the wild-type, indicating that SULT1A1/1A2 play a central role for FFA bioactivation also in humans. The excellent correlation between adduct levels in hepatic DNA and hemoglobin (r 2 = 0.97) indicated that 2-sulfoxymethylfuran of hepatic origin is sufficiently stable to enter circulation and pass the cellular membrane of erythrocytes. This is a prerequisite for the application of FFA-Val as a biomarker of internal FFA exposure.