Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II.
Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II.
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DOI：
10.1007/s00204-016-1726-7
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发表时间：
2017-01
影响因子：
6.1
通讯作者：
Marko D
中科院分区：
文献类型：
--
作者：
Jarolim K;Del Favero G;Pahlke G;Dostal V;Zimmermann K;Heiss E;Ellmer D;Stark TD;Hofmann T;Marko D
真菌毒素互变毒素I和II（ATX I和II）是由链格孢菌真菌产生的次级代谢产物，可能作为食品和饲料污染物出现，特别是在长时间储存后。虽然先前已经研究了变构毒素的毒性潜力，但对在其细胞内代谢中起作用的途径知之甚少。为了鉴定ATX I和ATX II的潜在靶标，在哺乳动物细胞中测试了这两种毒素与核因子红细胞衍生的2-样2/抗氧化剂应答元件（Nrf 2/ARE）途径的相互作用。该途径可被各种应激源激活，导致对代谢和解毒重要的酶的表达。在本研究中，仅ATX II触发Nrf 2-ARE依赖性荧光素酶表达的浓度依赖性增加。一致地，共聚焦显微镜显示在HT 29肠细胞中ATX II诱导的Nrf 2信号增加。与这些数据一致，ATX II诱导γ-谷氨酸半胱氨酸连接酶的转录，γ-谷氨酸半胱氨酸连接酶是催化细胞GSH合成的关键酶，并受Nrf 2调节。进一步研究表明，ATX II在短孵育时间（3 h）后诱导细胞GSH水平的浓度依赖性耗竭，并在长孵育时间（24 h）后升高。总之，证明了ATX II可以在哺乳动物细胞中的Nrf 2-ARE途径的几个水平上相互作用，并且ATX I不具有相同的作用机制。本文的在线版本（doi：10.1007/s 00204 -016-1726-7）包含补充材料，可供授权用户使用。
The mycotoxins altertoxin I and II (ATX I and II) are secondary metabolites produced by Alternaria alternata fungi and may occur as food and feed contaminants, especially after long storage periods. Although the toxic potential of altertoxins has been previously investigated, little is known about the pathways that play a role in their intracellular metabolism. In order to identify potential targets of ATX I and ATX II, the two toxins were tested for interaction with the nuclear factor erythroid-derived 2-like 2/antioxidant response element (Nrf2/ARE) pathway in mammalian cells. This pathway can be activated by various stressors resulting in the expression of enzymes important for metabolism and detoxification. In the present study, only ATX II triggered a concentration-dependent increase in Nrf2-ARE-dependent luciferase expression. Consistently, confocal microscopy revealed an ATX II-induced increase in Nrf2 signal in HT29 intestinal cells. In agreement with these data, ATX II induced the transcription of γ-glutamate cysteine ligase, the key enzyme in catalyzing GSH synthesis of the cells and which is regulated by Nrf2. Further investigations demonstrated that ATX II induced a concentration-dependent depletion of the cellular GSH levels after short incubation time (3 h) and an increase after longer incubation time (24 h). In conclusion, it was demonstrated that ATX II can interact at several levels of the Nrf2-ARE pathway in mammalian cells and that ATX I does not share the same mechanism of action. The online version of this article (doi:10.1007/s00204-016-1726-7) contains supplementary material, which is available to authorized users.