Detection of DNA Adducts Derived from the Reactive Metabolite of Furan, cis-2-Butene-1,4-dial

Furan is a toxic and carcinogenic compound used in industry and commonly found in the environment. The mechanism of furan's carcinogenesis is not well-understood and may involve both genotoxic and nongenotoxic pathways. Furan undergoes oxidation by cytochrome P450 to cis-2-butene-1,4-dial, whic...

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Bibliographic Details
Published in:Chemical research in toxicology 2006-03, Vol.19 (3), p.414-420
Main Authors: Byrns, Michael C, Vu, Choua C, Neidigh, Jonathan W, Abad, José-Luis, Jones, Roger A, Peterson, Lisa A
Format: Article
Language:English
Subjects:
Aldehydes - analysis
Aldehydes - toxicity
Animals
Cattle
Chromatography, High Pressure Liquid
DNA - chemistry
DNA - drug effects
DNA Adducts - analysis
Indicators and Reagents
Magnetic Resonance Spectroscopy
Reference Standards
Salmonella typhimurium - drug effects
Salmonella typhimurium - metabolism
Spectrometry, Mass, Electrospray Ionization
Spectrophotometry, Ultraviolet
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Summary:Furan is a toxic and carcinogenic compound used in industry and commonly found in the environment. The mechanism of furan's carcinogenesis is not well-understood and may involve both genotoxic and nongenotoxic pathways. Furan undergoes oxidation by cytochrome P450 to cis-2-butene-1,4-dial, which is thought to mediate furan's toxic effects. Consistently, cis-2-butene-1,4-dial readily reacts with glutathione, amino acids, and nucleosides. To determine the importance of DNA alkylation in furan-induced carcinogenesis, we developed an assay for the detection of cis-2-butene-1,4-dial-derived DNA adducts. DNA samples were treated with O-benzyl-hydroxylamine, which reacts with the aldehyde functionality of the DNA adducts. Enzyme hydrolysates of these samples were then analyzed by capillary electrospray tandem mass spectrometry with selected reaction monitoring. The dCyd and dAdo adducts were detected in digests of DNA treated with nanomolar concentrations of cis-2-butene-1,4-dial. In addition, these adducts were present in DNA isolated from Ames assay strain TA104 treated with mutagenic concentrations of cis-2-butene-1,4-dial. These data support the hypothesis that cis-butene-1,4-dial is a genotoxic metabolite of furan. This method will allow us to explore the role of these adducts in furan-induced carcinogenesis.
ISSN:0893-228X
1520-5010
DOI:10.1021/tx050302k