Metabolic activation of furfuryl alcohol: formation of 2-methylfuranyl DNA adducts in Salmonella typhimurium strains expressing human sulfotransferase 1A1 and in FVB/N mice
Metabolic activation of furfuryl alcohol: formation of 2-methylfuranyl DNA adducts in Salmonella typhimurium strains expressing human sulfotransferase 1A1 and in FVB/N mice
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DOI：
10.1093/carcin/bgr126
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发表时间：
2011-10-01
期刊：
影响因子：
4.7
通讯作者：
Glatt, Hansruedi
中科院分区：
文献类型：
--
作者：
Monien, Bernhard H.;Herrmann, Kristin;Glatt, Hansruedi
戊糖经酸和热诱导脱水形成的糠醇存在于许多食品中。在国家毒理学计划（NTP）的一项研究中，它在雄性B6 C3 F1小鼠中诱导肾小管肿瘤，在雄性F344/N大鼠中诱导鼻肿瘤。然而，在标准艾姆斯试验和一组体内致突变性试验中，糠醇呈阴性。在这里，我们表明，糠醇是诱变鼠伤寒沙门氏菌TA 100工程表达的人磺基转移酶（SULT）1A 1。这一发现表明，糠醇通过细胞内磺基缀合转化为2-磺基-氧甲基呋喃，一种与DNA反应的亲电试剂。我们检测了猪肝DNA与新鲜制备的2-磺基氧甲基呋喃孵育后，2 '-脱氧腺苷、2'-脱氧鸟苷和2 '-脱氧胞苷的核苷加合物。合成了主要加合物N-2-（（呋喃-2-基）甲基）-2 '-脱氧鸟苷（N-2-MFdG）和N-6-（（呋喃-2-基）甲基）-2'-脱氧腺苷（N-6-MFdA）。其结构经核磁共振和质谱确证。液相色谱-串联质谱法定量的两个加合物的设计。在暴露于糠醇的表达SULT 1A 1的鼠伤寒沙门氏菌TA 100的DNA中以及通过饮用水接受类似于390 mg糠醇/kg体重/天的FVB/N小鼠的肝、肺和肾的DNA中检测到N-2-MFdG和N-6-MFdA。总之，通过磺基缀合将糠醇转化为诱变剂。在经糠醇处理的小鼠肾DNA中检测到N-2-MFdG和N-6-MFdA，表明在NTP研究中在该组织中观察到的肿瘤可能是由2-磺基氧甲基呋喃诱导的。
Furfuryl alcohol, formed by acid- and heat-induced dehydration from pentoses, is found in many foodstuffs. It induced renal tubule neoplasms in male B6C3F1 mice and nasal neoplasms in male F344/N rats in a study of the National Toxicology Program (NTP). However, furfuryl alcohol was negative in the standard Ames test and in a battery of in vivo mutagenicity tests. Here, we show that furfuryl alcohol is mutagenic in Salmonella typhimurium TA100 engineered for expression of human sulfotransferase (SULT) 1A1. This finding suggests that furfuryl alcohol is converted by intracellular sulfo conjugation to 2-sulfo-oxymethylfuran, an electrophile reacting with DNA. We detected nucleoside adducts of 2'-deoxyadenosine, 2'-deoxyguanosine and 2'-deoxycytidine in porcine liver DNA incubated with freshly prepared 2-sulfo-oxymethylfuran. The main adducts, N-2-((furan-2-yl)methyl)-2'-deoxyguanosine (N-2-MFdG) and N-6-((furan-2-yl)methyl)-2'-deoxyadenosine (N-6-MFdA) were synthesized. Their structures were verified by NMR and mass spectrometry. Liquid chromatography-tandem mass spectrometry methods for the quantification of both adducts were devised. N-2-MFdG and N-6-MFdA were detected in DNA of furfuryl alcohol-exposed S.typhimurium TA100 expressing SULT1A1 and in DNA of liver, lung and kidney of FVB/N mice that had received similar to 390 mg furfuryl alcohol/kg body wt/day via the drinking water for 28 days. In summary, furfuryl alcohol is converted by sulfo conjugation to a mutagen. The detection of N-2-MFdG and N-6-MFdA in renal DNA of furfuryl alcohol-treated mice suggests that the neoplasms observed in this tissue in the study of the NTP may have been induced by 2-sulfo-oxymethylfuran.