Pahlke G, Tiessen C, Domnanich K, Kahle N, Groh I A M, Schreck I, Weiss C, Marko D
Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
Toxicol Lett. 2016 Jan 5;240(1):93-104. doi: 10.1016/j.toxlet.2015.10.003. Epub 2015 Oct 22.
The Alternaria toxins alternariol (AOH) and alternariol monomethyl ether (AME) have been reported previously to act as activators of the aryl hydrocarbon receptor (AhR) in murine hepatoma cells, thus enhancing the expression of cytochrome P450 (CYP) 1A monooxygenases. Concomitantly, both benzopyrones represent substrates of CYP1A, giving rise to catecholic metabolites. The impact of AOH and AME on CYP1A expression in human cells of different tissue origin colon (HT29), esophagus (KYSE510), liver (HepG2) and their effects on cell viability, generation of reactive oxygen species (ROS) and DNA integrity were investigated. ROS production was induced by both mycotoxins in all cell lines with AOH exhibiting the highest potency in esophageal cells concomitant with the most prominent CYP1A induction level. Of note, altertoxin-II (ATX-II), the more potent DNA-damaging mutagen formed by Alternaria alternata, induces CYP1A even at significant lower concentrations. AhR-siRNA knockdown in human esophageal cells supported the hypothesis of AhR-mediated CYP1A1 induction by AOH. However, DNA damage was minor at CYP1A1-inducing AOH concentrations. AhR-depletion did not affect the DNA-damaging properties of AOH indicating no substantial impact of AhR in this regard. However, in combination with xenobiotics prone to metabolic activation by CYP1A the induction of CYP1A by Alternaria toxins deserves further attention.
先前已有报道称，链格孢菌毒素交链孢酚（AOH）和交链孢酚单甲醚（AME）可作为小鼠肝癌细胞中芳烃受体（AhR）的激活剂，从而增强细胞色素P450（CYP）1A单加氧酶的表达。同时，这两种苯并吡喃都是CYP1A的底物，可产生儿茶酚代谢物。研究了AOH和AME对不同组织来源的人结肠（HT29）、食管（KYSE510）、肝脏（HepG2）细胞中CYP1A表达的影响，以及它们对细胞活力、活性氧（ROS）生成和DNA完整性的影响。两种霉菌毒素均在所有细胞系中诱导ROS生成，其中AOH在食管细胞中诱导能力最强，同时CYP1A诱导水平也最为显著。值得注意的是，链格孢菌产生的更具DNA损伤性的诱变剂——变应毒素-II（ATX-II），即使在浓度显著较低时也能诱导CYP1A。在人食管细胞中敲低AhR-siRNA支持了AOH通过AhR介导诱导CYP1A1的假说。然而，在诱导CYP1A1的AOH浓度下，DNA损伤较小。AhR缺失并不影响AOH的DNA损伤特性，表明AhR在这方面没有实质性影响。然而，鉴于AOH与易于被CYP1A代谢激活的异源生物结合，链格孢菌毒素对CYP1A的诱导值得进一步关注。
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