Department of Food Chemistry and Toxicology, University of Vienna, 1090 Vienna, Italy.
Chair of Analytical Chemistry, Technical University of Munich, 80333 Munich, Germany.
Biomolecules. 2020 Jul 9;10(7):1018. doi: 10.3390/biom10071018.
molds simultaneously produce a large variety of mycotoxins, of which several were previously reported to induce enzymes of phase I metabolism through aryl hydrocarbon receptor activation. Thus, we investigated the potential of naturally occurring toxin mixtures to induce Cytochrome P450 (CYP) 1A1/1A2/1B1 activity. Two variants of an extract from cultured as well as the toxins alternariol (AOH), alternariol monomethyl ether (AME), altertoxin I (ATX-I), and altertoxin II (ATX-II), were tested singularly and in binary mixtures applying the 7-ethoxy-resorufin--deethylase (EROD) assay in MCF-7 breast cancer cells. Sub-cytotoxic concentrations of the two toxin mixtures, as well as ATX-I, ATX-II and AOH, exhibited dose-dependent enhancements of CYP 1 activity. ATX-I and ATX-II interacted synergistically in this respect, demonstrating the two perylene quinones as major contributors to the extract's potential. Binary mixtures between AOH and the two altertoxins respectively exhibited concentration-dependent antagonistic as well as synergistic combinatory effects. Notably, AME showed no efficacy towards EROD enzyme activity or impact on other toxins' efficacy. Hence, this study provides insights into synergistic and other combinatory effects of toxins in natural co-occurrence scenarios in the context of AhR signalling pathway activation in breast cancer cells.
霉菌同时产生多种霉菌毒素，其中一些先前被报道通过芳基烃受体激活诱导 I 相代谢酶。因此，我们研究了天然存在的毒素混合物诱导细胞色素 P450（CYP）1A1/1A2/1B1 活性的潜力。从培养的中提取的两种变体以及交替醇（AOH）、交替醇单甲基醚（AME）、交替曲霉素 I（ATX-I）和交替曲霉素 II（ATX-II）毒素，分别进行了测试，并在 MCF-7 乳腺癌细胞中应用 7-乙氧基-Resorufin-O-脱乙基酶（EROD）测定法进行了二元混合物测试。两种毒素混合物以及 ATX-I、ATX-II 和 AOH 的亚细胞毒性浓度均表现出 CYP 1 活性的剂量依赖性增强。在这方面，ATX-I 和 ATX-II 相互协同作用，表明这两种邻苯二甲酸醌是提取物潜在作用的主要贡献者。AOH 和两种 altertoxins 之间的二元混合物分别表现出浓度依赖性的拮抗和协同组合效应。值得注意的是，AME 对 EROD 酶活性或对其他毒素功效没有影响。因此，这项研究为芳基烃受体信号通路激活背景下乳腺癌细胞中天然共存情况下霉菌毒素的协同和其他组合效应提供了深入了解。
