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Hemoglobin adducts of furfuryl alcohol in genetically modified mouse models: Role of endogenous sulfotransferases 1a1 and 1d1 and transgenic human sulfotransferases 1A1/1A2



Hemoglobin adducts of furfuryl alcohol in genetically modified mouse models: Role of endogenous sulfotransferases 1a1 and 1d1 and transgenic human sulfotransferases 1A1/1A2



Toxicology Letters 295: 173-178



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 (r2 = 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.

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Accession: 065188839

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PMID: 29908303

DOI: 10.1016/j.toxlet.2018.06.008


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