Ethanol and 4-methylpyrazole increase DNA adduct formation of furfuryl alcohol in FVB/N wild-type mice and in mice expressing human sulfotransferases 1A1/1A2
Abstract
Furfuryl alcohol (FFA) is a carcinogenic food contaminant, which is formed by acid- and heat-catalyzed degradation of fructose and glucose. The activation by sulfotransferases (SULTs) yields a DNA reactive and mutagenic sulfate ester. The most prominent DNA adduct, N(2)-((furan-2-yl)methyl)-2'-deoxyguanosine (N(2)-MF-dG), was detected in FFA-treated mice and also in human tissue samples. The dominant pathway of FFA detoxification is the oxidation via alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs). The activity of these enzymes may be greatly altered in the presence of inhibitors or competitive substrates. Here, we investigated the impact of ethanol and the ADH inhibitor 4-methylpyrazole (4MP) on the DNA adduct formation by FFA in wild-type and in humanized mice that were transgenic for human SULT1A1/1A2 and deficient in the mouse (m) Sult1a1 and Sult1d1 genes (h1A1/1A2/1a1(-)/1d1(-)). The administration of FFA alone led to hepatic adduct levels of 4.5 N(2)-MF-dG/10(8) nucleosides and 33.6 N(2)-MF-dG/10(8) nucleosides in male and female wild-type mice, respectively, and of 19.6 N(2)-MF-dG/10(8) nucleosides and 95.4 N(2)-MF-dG/10(8) nucleosides in male and female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 1.6g ethanol/kg body weight increased N(2)-MF-dG levels by 2.3-fold in male and by 1.7-fold in female wild-type mice and by 2.5-fold in male and by 1.5-fold in female h1A1/1A2/1a1(-)/1d1(-) mice. The coadministration of 100mg 4MP/kg body weight had a similar effect on the adduct levels. These findings indicate that modulators of the oxidative metabolism, e.g. the drug 4MP or consumption of alcoholic beverages, may increase the genotoxic effects of FFA also in humans.
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Free amino acid residues of proteins, lipids, nucleic acids, and nucleophilic molecules are major targets of adduct formation or covalent binding with reactive molecules such as acetaldehyde, acrolein, crotonaldehyde, formaldehyde, malondialdehyde, 4-hydroxynonenal, 8-hydroxydeoxyguanosine, N2-((furan-2-yl)methyl)-2′-deoxyguanosine, and N2-ethyl-2′-deoxyguanosine.
“Free amino acid residues of proteins, lipids, nucleic acids, and nucleophilic molecules are major targets of adduct formation or covalent binding with reactive molecules such as acetaldehyde, acrolein, crotonaldehyde, formaldehyde, malondialdehyde, 4-hydroxynonenal, 8-hydroxydeoxyguanosine, N2-((furan-2-yl)methyl)-2′-deoxyguanosine, and N2-ethyl-2′-deoxyguanosine164–166.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [165]
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- Authors
- Sachse, B., Meinl, W., Glatt, H., & Monien, B. H.
- Affiliations
- German Institute of Human Nutrition (DE)
- German Federal Institute for Risk Assessment (BfR) (DE)
- Corresponding author
- Monien, Bernhard H.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2016-01-16
- Volume
- 37
- Issue
- 3
- Pages
- 314-319
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- OpenAlex
- W2266457389
- Cited by
- 12
- References
- 39
- Citations by year
- 2025: 1 · 2024: 2 · 2022: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2018: 2 · 2017: 1 · 2016: 2
- FWCI
- 0.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Carcinogenesis (publishedVersion)
- PubMed (publishedVersion)
- HighWire Press Open Archive (submittedVersion)
- OpenAgrar (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- furfuryl alcohol, DNA adduct formation, sulfotransferase, humanized mice, ethanol, 4-methylpyrazole, alcohol dehydrogenase inhibition, aldehyde dehydrogenase, food contaminants, DNA adducts, SULT1A1
- MeSH terms
- Fomepizole, Ethanol, Animals, Chromatography, Liquid, DNA Damage, Female, Furans, Humans, Liver, Male, Mice, Inbred Strains, Mice, Transgenic, Mutagens, Pyrazoles, Arylsulfotransferase, DNA Adducts, Mice, Tandem Mass Spectrometry
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