Division of Environmental Health Sciences, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Chem Res Toxicol. 2011 Nov 21;24(11):1924-36. doi: 10.1021/tx200273z. Epub 2011 Sep 12.
Furan is toxic and carcinogenic in rodents. Because of the large potential for human exposure, furan is classified as a possible human carcinogen. The detailed mechanism by which furan causes toxicity and cancer is not yet known. Since furan toxicity requires cytochrome P450-catalyzed oxidation of furan, we have characterized the urinary and hepatocyte metabolites of furan to gain insight into the chemical nature of the reactive intermediate. Previous studies in hepatocytes indicated that furan is oxidized to the reactive α,β-unsaturated dialdehyde, cis-2-butene-1,4-dial (BDA), which reacts with glutathione (GSH) to form 2-(S-glutathionyl)succinaldehyde (GSH-BDA). This intermediate forms pyrrole cross-links with cellular amines such as lysine and glutamine. In this article, we demonstrate that GSH-BDA also forms cross-links with ornithine, putrescine, and spermidine when furan is incubated with rat hepatocytes. The relative levels of these metabolites are not completely explained by hepatocellular levels of the amines or by their reactivity with GSH-BDA. Mercapturic acid derivatives of the spermidine cross-links were detected in the urine of furan-treated rats, which indicates that this metabolic pathway occurs in vivo. Their detection in furan-treated hepatocytes and in urine from furan-treated rats indicates that polyamines may play an important role in the toxicity of furan.
糠醛在啮齿动物中具有毒性和致癌性。由于人类暴露的潜在风险很大，糠醛被归类为可能的人类致癌物。糠醛导致毒性和癌症的详细机制尚不清楚。由于糠醛毒性需要细胞色素 P450 催化氧化糠醛，我们已经对糠醛的尿和肝细胞代谢物进行了表征，以深入了解反应性中间产物的化学性质。先前在肝细胞中的研究表明，糠醛被氧化为反应性的α，β-不饱和二醛，顺式-2-丁烯-1,4-二醛（BDA），它与谷胱甘肽（GSH）反应形成 2-（S-谷胱甘肽基）琥珀醛（GSH-BDA）。这种中间产物与赖氨酸和谷氨酸等细胞内胺形成吡咯交联。在本文中，我们证明当糠醛与大鼠肝细胞孵育时，GSH-BDA 还与鸟氨酸、腐胺和精胺形成交联。这些代谢物的相对水平不能完全用细胞内胺的水平或它们与 GSH-BDA 的反应性来解释。在糠醛处理的大鼠尿液中检测到精胺交联的巯基尿酸衍生物，这表明该代谢途径在体内发生。它们在糠醛处理的肝细胞和糠醛处理的大鼠尿液中的检测表明，多胺可能在糠醛的毒性中起重要作用。
