Reactivity of the 2-Methylfuran Phase I Metabolite 3-Acetylacrolein Toward DNA.

IF 5.7 1区 农林科学 Q1 AGRICULTURE, MULTIDISCIPLINARY
Verena Schäfer, Simone Stegmüller, Hanna Becker, Elke Richling
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Abstract

2-Methylfuran (2-MF) is a well-known industrial chemical and also formed via thermal treatment of food. One main source of 2-MF in the human diet is coffee. 2-MF is known to form 3-acetylacrolein (AcA, 4-oxopent-2-enal) via cytochrome P 450 metabolism and further reacts with amino acids in vivo. Still the reactivity toward other biomolecules is rather scarce. Therefore, AcA was synthesized, and its reaction with 2'-deoxyadenosine (dA), 2'deoxyguanosine (dG), 2'deoxycytosine (dC), and 2'-deoxythymidine (dT) was tested. For this purpose, adduct formation was performed by acid hydrolysis of 2,5-dihydro-2,5-dimethoxy-2-methylfuran (DHDMMF) as well as pure AcA. The structures of these adducts were confirmed by UPLC-ESI+-MS/MS fragmentation patterns and 1H-/13CNMR spectra. Except for dT, which showed no reactivity, all adducts of AcA were characterized, which enabled the development of sensitive quantification methods via (U)HPLC-ESI±-MS/MS. Pure AcA was synthesized by oxidation of 2-MF using dimethyldioxirane (DMDO), and its behavior in aqueous medium was studied. Incubations of AcA and isolated DNA of primary rat hepatocytes (pRH) showed time- and dose-dependent formation of the identified DNA adducts dA-AcA, dG-AcA, or dC-AcA. In contrast, the DNA adducts dA-AcA, dG-AcA, or dC-AcA were not detected on a cellular level when pRH were incubated with 2-MF or AcA. This indicates an efficient detoxification or reaction with biomolecules in the cell, although the induction of other DNA damage, possibly also by other metabolites, cannot be ruled out in principle.

Abstract Image

2-Methylfuran Phase I Metabolite 3-Acetylacrolein 与 DNA 的反应性。
2-甲基呋喃(2-MF)是一种著名的工业化学品,也可通过热处理食物形成。人类饮食中 2-MF 的一个主要来源是咖啡。已知 2-MF 可通过细胞色素 P 450 代谢生成 3-乙酰基丙烯醛(AcA,4-氧代戊-2-烯醛),并进一步与体内的氨基酸发生反应。但是,这种物质对其他生物大分子的反应性还很少。因此,我们合成了 AcA,并测试了它与 2'-脱氧腺苷(dA)、2'-脱氧鸟苷(dG)、2'-脱氧胞嘧啶(dC)和 2'-脱氧胸苷(dT)的反应。为此,通过酸水解 2,5-二氢-2,5-二甲氧基-2-甲基呋喃(DHDMMF)和纯 AcA 来形成加合物。UPLC-ESI+-MS/MS 片段模式和 1H-/13CNMR 光谱证实了这些加合物的结构。除了 dT 没有反应外,所有 AcA 的加合物都得到了表征,从而可以通过 (U)HPLC-ESI±-MS/MS 开发出灵敏的定量方法。利用二甲基二氧环己烷(DMDO)氧化 2-MF 合成了纯 AcA,并研究了它在水介质中的行为。将 AcA 与原代大鼠肝细胞(pRH)分离出的 DNA 进行孵育,结果显示 DNA 加合物 dA-AcA、dG-AcA 或 dC-AcA 的形成具有时间和剂量依赖性。相反,当 pRH 与 2-MF 或 AcA 一起培养时,在细胞水平上检测不到 DNA 加合物 dA-AcA、dG-AcA 或 dC-AcA。这表明细胞内的解毒或与生物分子的反应是有效的,但原则上不能排除其他代谢物也可能诱发其他 DNA 损伤。
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来源期刊
Journal of Agricultural and Food Chemistry
Journal of Agricultural and Food Chemistry 农林科学-农业综合
CiteScore
9.90
自引率
8.20%
发文量
1375
审稿时长
2.3 months
期刊介绍: The Journal of Agricultural and Food Chemistry publishes high-quality, cutting edge original research representing complete studies and research advances dealing with the chemistry and biochemistry of agriculture and food. The Journal also encourages papers with chemistry and/or biochemistry as a major component combined with biological/sensory/nutritional/toxicological evaluation related to agriculture and/or food.
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