Impact of Alternaria toxins on CYP1A1 expression in different human tumor cells and relevance for genotoxicity

被引：32
作者：
Pahlke, G. [1 ]
Tiessen, C. [1 ]
Domnanich, K. [1 ]
Kahle, N. [1 ]
Groh, I. A. M. [1 ]
Schreck, I. [2 ]
Weiss, C. [2 ]
Marko, D. [1 ]
机构：
[1] Univ Vienna, Dept Food Chem & Toxicol, A-1090 Vienna, Austria
[2] Karlsruhe Inst Technol KIT, Inst Toxicol & Genet ITG, Karlsruhe, Germany
来源：
TOXICOLOGY LETTERS | 2016年 / 240卷 / 01期
关键词：
Alternariol; Alternariol monomethyl ether; Altertoxin-II; CYP1A; Aryl hydrocarbon receptor; Genotoxicity; ARYL-HYDROCARBON RECEPTOR; CULTURED-MAMMALIAN-CELLS; PRIMARY HUMAN HEPATOCYTES; IN-VITRO; MYCOTOXINS ALTERNARIOL; ALTERTOXIN-II; METHYL-ETHER; OXIDATIVE STRESS; MUTAGENICITY; QUANTITIES;
D O I：
10.1016/j.toxlet.2015.10.003
中图分类号：
R99 [毒物学（毒理学）];
学科分类号：
100405 ;
摘要：
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. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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页码：93 / 104
页数：12
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