title: Impact of Alternaria toxins on CYP1A1 expression in different human tumor cells and relevance for genotoxicity.
abstract: 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.
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria. Electronic address: gudrun.pahlke@univie.ac.at.
authors.forename: G
authors.initials: G
authors.lastname: Pahlke
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
authors.forename: C
authors.initials: C
authors.lastname: Tiessen
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Domnanich
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
authors.forename: N
authors.initials: N
authors.lastname: Kahle
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
authors.forename: I A M
authors.initials: IA
authors.lastname: Groh
authors.affiliation: Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schreck
authors.affiliation: Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Germany.
authors.forename: C
authors.initials: C
authors.lastname: Weiss
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringer Str. 38, A-1090 Vienna, Austria.
authors.forename: D
authors.initials: D
authors.lastname: Marko
mesh_terms: D000528:Alternaria / Q000378:metabolism*; D001551:Benz(a)Anthracenes / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020552:Comet Assay; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D005786:Gene Expression Regulation; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D007783:Lactones / Q000633:toxicity; D009183:Mycotoxins / Q000633:toxicity*; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism
chemical_list: D001551:Benz(a)Anthracenes; D007783:Lactones; D009183:Mycotoxins; D017382:Reactive Oxygen Species; D018336:Receptors, Aryl Hydrocarbon; C050234:altertoxin II; C569463:CYP1A1 protein, human; D019363:Cytochrome P-450 CYP1A1; C005197:alternariol; C018206:alternariol monomethyl ether
keywords: Alternariol; Alternariol monomethyl ether; Altertoxin-II; Aryl hydrocarbon receptor; CYP1A; Genotoxicity