Division of Environmental Health Sciences and Masonic Cancer Center, University of Minnesota, Mayo Mail Code 806, 420 Delaware Street Southeast, Minneapolis, Minnesota 55455, USA.
Chem Res Toxicol. 2010 Jan;23(1):142-51. doi: 10.1021/tx9003215.
Furan is a rodent hepatotoxicant and carcinogen. Because this compound is an important industrial intermediate and has been detected in heat-processed foods and smoke, humans are likely exposed to this toxic compound. Characterization of urinary metabolites of furan will lead to the development of biomarkers to assess human health risks associated with furan exposure. Previous studies indicate that furan is oxidized to a reactive alpha,beta-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA), in a reaction catalyzed by cytochrome P450. Five previously characterized metabolites are derived from the reaction of BDA with cellular nucleophiles such as glutathione and protein. They include the monoglutathione reaction product, N-[4-carboxy-4-(3-mercapto-1H-pyrrol-1-yl)-1-oxobutyl]-l-cysteinylglycine cyclic sulfide, and its downstream metabolite, S-[1-(1,3-dicarboxypropyl)-1H-pyrrol-3-yl]methylthiol, as well as (R)-2-acetylamino-6-(2,5-dihydro-2-oxo-1H-pyrrol-1-yl)-1-hexanoic acid and N-acetyl-S-[1-(5-acetylamino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine and its sulfoxide. The last two compounds are downstream metabolites of a BDA-derived cysteine-lysine cross-link, S-[1-(5-amino-5-carboxypentyl)-1H-pyrrol-3-yl]-l-cysteine. In this report, we present the characterization of seven additional urinary furan metabolites, all of which are derived from this cross-link. The cysteinyl residue is subject to several biotransformation reactions, including N-acetylation and S-oxidation. Alternatively, it can undergo beta-elimination followed by S-methylation to a methylthiol intermediate that is further oxidized to a sulfoxide. The lysine portion of the cross-link either is N-acetylated or undergoes a transamination reaction to generate an alpha-ketoacid metabolite that undergoes oxidative decarboxylation. Some of these metabolites are among the most abundant furan metabolites present in urine as judged by LC-MS/MS analysis, indicating that the oxidation of furan to BDA and BDA's subsequent reaction with cellular cysteine and lysine residues may represent a significant in vivo pathway of furan biotransformation. Because they are derived from cellular BDA reaction products, these metabolites are markers of furan exposure and bioactivation and could be explored as potential biomarkers in human studies.
呋喃是一种啮齿动物肝毒素和致癌物质。由于这种化合物是一种重要的工业中间体，并且已经在热加工食品和烟雾中检测到，因此人类可能会接触到这种有毒化合物。呋喃代谢产物的特征将导致开发生物标志物来评估与呋喃暴露相关的人类健康风险。先前的研究表明，呋喃在细胞色素 P450 催化下氧化为反应性α，β-不饱和二醛，顺式-2-丁烯-1,4-二醛（BDA）。先前已鉴定的五种代谢产物源自 BDA 与细胞亲核试剂（如谷胱甘肽和蛋白质）的反应。它们包括单谷胱甘肽反应产物，N-[4-羧基-4-（3-巯基-1H-吡咯-1-基）-1-氧代丁基]-L-半胱氨酸甘氨酸环硫醚，及其下游代谢产物，S-[1-（1,3-二羧基丙基）-1H-吡咯-3-基]甲基硫醇，以及（R）-2-乙酰氨基-6-（2,5-二氢-2-氧代-1H-吡咯-1-基）-1-己酸和 N-乙酰-S-[1-（5-乙酰氨基-5-羧基戊基）-1H-吡咯-3-基]-L-半胱氨酸及其亚砜。最后两种化合物是 BDA 衍生的半胱氨酸-赖氨酸交联的下游代谢产物，S-[1-（5-氨基-5-羧基戊基）-1H-吡咯-3-基]-L-半胱氨酸。在本报告中，我们介绍了另外七种尿中呋喃代谢物的特征，它们均源自该交联物。半胱氨酸残基会发生几种生物转化反应，包括 N-乙酰化和 S-氧化。或者，它可以进行β消除，然后进行 S-甲基化，生成甲基硫醇中间体，然后进一步氧化为亚砜。交联的赖氨酸部分要么被 N-乙酰化，要么发生转氨反应，生成α-酮酸代谢物，然后进行氧化脱羧。根据 LC-MS/MS 分析，其中一些代谢物是尿液中含量最丰富的呋喃代谢物之一，这表明呋喃氧化为 BDA 以及 BDA 随后与细胞内半胱氨酸和赖氨酸残基的反应可能是呋喃生物转化的重要体内途径。由于它们是源自细胞 BDA 反应产物，因此这些代谢产物是呋喃暴露和生物活化的标志物，可以作为人类研究中的潜在生物标志物进行探索。
