Institute of Food Chemistry, Westfälische Wilhelms-Universität, Münster, Germany.
Mol Nutr Food Res. 2013 Mar;57(3):516-22. doi: 10.1002/mnfr.201200465. Epub 2012 Dec 23.
Fumonisins are mycotoxins produced by Fusarium species. The predominant derivative, fumonisin B1 (FB1), occurs in food and feed and is of health concern due to its hepatotoxic and carcinogenic effects. However, the role of FB1 metabolites on the mechanism of the toxicity, the inhibition of the ceramide synthesis, is unknown. The aim of this study was to identify new fumonisin metabolites and to evaluate their cytotoxic potential.
MS, molecular biology, and in vitro enzyme assays were used to investigate fumonisin metabolism in mammalian cells overexpressing human ceramide synthase (CerS) genes. N-acyl-FB1 derivatives were detected as new metabolites in cultured cells at levels of up to 10 pmol/mg of protein. The N-acylation of FB1 and hydrolyzed FB1 was analyzed in several cell lines, including cells overexpressing CerS. The acyl-chain length of the N-acyl fumonisins depends on the CerS isoform acylating them. The N-acyl fumonisins are more cytotoxic than the parent fumonisin B1.
The identification of N-acyl fumonisins with various acyl chain lengths together with the observed cytotoxicity of these compounds is a new aspect of fumonisin-related toxicity. Therefore, these new metabolites might play an important role in the mode of action of fumonisins.
伏马菌素是由镰刀菌属产生的真菌毒素。主要衍生物，伏马菌素 B1（FB1），存在于食物和饲料中，由于其肝毒性和致癌作用，引起了人们的健康关注。然而，FB1 代谢物在毒性机制、神经酰胺合成抑制方面的作用尚不清楚。本研究的目的是鉴定新的伏马菌素代谢物并评估其细胞毒性潜力。
采用 MS、分子生物学和体外酶测定法，研究了在过表达人神经酰胺合酶（CerS）基因的哺乳动物细胞中伏马菌素的代谢。在培养细胞中检测到高达 10 pmol/mg 蛋白水平的 N-酰基-FB1 衍生物作为新的代谢物。在包括过表达 CerS 的细胞在内的几种细胞系中分析了 FB1 和水解 FB1 的 N-酰化。N-酰基伏马菌素的酰链长度取决于酰化它们的 CerS 同工型。N-酰基伏马菌素比母体伏马菌素 B1 具有更高的细胞毒性。
鉴定出具有不同酰链长度的 N-酰基伏马菌素以及这些化合物的观察到的细胞毒性是伏马菌素相关毒性的一个新方面。因此，这些新的代谢物可能在伏马菌素的作用模式中发挥重要作用。
