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

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• 作者：Michael C. Byrns ; Choua C. Vu ; Jonathan W. Neidigh ; José ; -Luis Abad ; Roger A. Jones ; and Lisa A. Peterson
• 刊名：Chemical Research in Toxicology
• 出版年：2006
• 出版时间：March 2006
• 年：2006
• 卷：19
• 期：3
• 页码：414 - 420
• 全文大小：113K
• 年卷期：v.19,no.3(March 2006)
• ISSN：1520-5010

文摘

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 andnongenotoxic pathways. Furan undergoes oxidation by cytochrome P450 to cis-2-butene-1,4-dial, whichis 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-inducedcarcinogenesis, 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 functionalityof the DNA adducts. Enzyme hydrolysates of these samples were then analyzed by capillary electrospraytandem mass spectrometry with selected reaction monitoring. The dCyd and dAdo adducts were detectedin digests of DNA treated with nanomolar concentrations of cis-2-butene-1,4-dial. In addition, theseadducts were present in DNA isolated from Ames assay strain TA104 treated with mutagenic concentrationsof cis-2-butene-1,4-dial. These data support the hypothesis that cis-butene-1,4-dial is a genotoxic metaboliteof furan. This method will allow us to explore the role of these adducts in furan-induced carcinogenesis.