Characterization of amino acid on glutathione adducts of cis-2-butene-1,4-dial, a reactive metabolite of furan
Characterization of amino acid on glutathione adducts of cis-2-butene-1,4-dial, a reactive metabolite of furan
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DOI：
10.1021/tx9700174
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发表时间：
1997-08-01
影响因子：
4.1
通讯作者：
Peterson, LA
中科院分区：
文献类型：
--
作者：
Chen, LJ;Hecht, SS;Peterson, LA
肝癌原呋喃的代谢活化产生与蛋白质共价反应的代谢产物，顺式-2-丁烯-1，4-二醛是呋喃的微粒体代谢产物，这种反应性醛被认为是负责呋喃致癌活性的毒性代谢产物。为了表征这种不饱和二醛对蛋白质的烷基化作用，研究了顺式-2-丁烯-1，4-二醛与模型亲核试剂在pH7.4缓冲溶液中反应生成的产物：N-α-乙酰基-L-半胱氨酸（AcCys）与顺式-2-丁烯-1，4-二醛反应生成N-取代吡咯啉-2-酮加合物。N-乙酰-L-半胱氨酸（AcCys）与顺式-2-丁烯-1，4-二醛快速反应生成多种未知产物。在该反应混合物中包含AcLys产生连接两个氨基酸残基的N-取代的3-（S-乙酰基半胱氨酰基）吡咯加合物。当顺式-2-丁烯-1，4-二醛和谷胱甘肽（GSH）结合时，分离出相关化合物。在这种情况下，顺式-2-丁烯-1，4-二醛交联两个GSH分子，根据GSH的相对浓度产生环状或非环状加合物。在存在[甘氨酸-2-H-3]GSH的情况下，呋喃与大鼠肝微粒体孵育导致形成放射性峰，该峰与双谷胱甘肽结合物的合成标准品共洗脱。这些研究表明，在呋喃的微粒体氧化过程中形成的反应性顺式-2-丁烯-1，4-二醛与氨基酸残基快速完全反应，生成吡咯和吡咯啉-2-酮衍生物。因此，该代谢物是与蛋白质结合的活化呋喃衍生物的可能候选物。顺式-2-丁烯-1，4-二醛交联氨基酸的容易性表明吡咯-硫醇交联可能与呋喃暴露后观察到的毒性有关。
Metabolic activation of the hepatocarcinogen furan yields metabolites that react covalently with proteins, cis-2-Butene-1,4-dial is a microsomal metabolite of furan, This reactive aldehyde is thought to be the toxic metabolite that is responsible for the carcinogenic activity of furan. In order to characterize the chemistry by which this unsaturated dialdehyde could alkylate proteins, the products formed upon reaction of cis-2-butene-1,4-dial with model nucleophiles in PH 7.4 buffer were investigated, N-alpha-Acetyl-L-cysteine (AcCys) reacts with cis-2-butene-1,4-dial to form N-substituted pyrrolin-2-one adducts. N-Acetyl-L-cysteine (AcCys) reacts rapidly with cis-2-butene-1,4-dial to form multiple uncharacterized products. The inclusion of AcLys in this reaction mixture yielded an N-substituted 3-(S-acetylcysteinyl)pyrrole adduct which Links the two amino acid residues. Related compounds were isolated when cis-2-butene-1,4-dial and glutathione (GSH) were combined. In this case, cis-2-butene-1,4-dial cross-linked two molecules of GSH resulting in either cyclic or acyclic adducts depending on the relative GSH concentration. Incubation of furan with rat liver microsomes in the presence of [glycine-2-H-3]GSH led to the formation of radioactive peaks that coeluted with synthetic standards for the bisgluthathione conjugates. These studies demonstrate that the reactive cis-2-butene-1,4-dial formed during the microsomal oxidation of furan reacts rapidly and completely with amino acid residues to farm pyrrole and pyrrolin-2-one derivatives. Therefore, this metabolite is a likely candidate for the activated furan derivative that binds to proteins. The ease with which cis-2-butene-1,4-dial cross-links amino acids suggests that pyrrole-thiol cross-links may be involved in the toxicity observed following furan exposure.