title: Activation of the Nrf2-ARE pathway by the Alternaria alternata mycotoxins altertoxin I and II.
abstract: 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.
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Jarolim
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Del Favero
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Pahlke
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria.
authors.forename: Victoria
authors.initials: V
authors.lastname: Dostal
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Kristin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090, Vienna, Austria.
authors.forename: Elke
authors.initials: E
authors.lastname: Heiss
authors.affiliation: Chair of Food Chemistry and Molecular Sensory Science, TU München, Lise-Meitner-Straße 34, 85354, Freising, Germany.
authors.forename: Doris
authors.initials: D
authors.lastname: Ellmer
authors.affiliation: Chair of Food Chemistry and Molecular Sensory Science, TU München, Lise-Meitner-Straße 34, 85354, Freising, Germany.
authors.forename: Timo D
authors.initials: TD
authors.lastname: Stark
authors.affiliation: Chair of Food Chemistry and Molecular Sensory Science, TU München, Lise-Meitner-Straße 34, 85354, Freising, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hofmann
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Währinger Straße 38, 1090, Vienna, Austria. doris.marko@univie.ac.at.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
mesh_terms: D000528:Alternaria; D000818:Animals; D061745:Antioxidant Response Elements / Q000187:drug effects*; D001551:Benz(a)Anthracenes / Q000633:toxicity*; D016466:CHO Cells; D003412:Cricetulus; D005786:Gene Expression Regulation / Q000187:drug effects; D017930:Genes, Reporter / Q000187:drug effects*; D005721:Glutamate-Cysteine Ligase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D018613:Microscopy, Confocal; D009183:Mycotoxins / Q000633:toxicity*; D051267:NF-E2-Related Factor 2 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D010569:Perylene / Q000031:analogs & derivatives / Q000633:toxicity; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001551:Benz(a)Anthracenes; D009183:Mycotoxins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D011994:Recombinant Proteins; C050234:altertoxin II; C050233:altertoxin I; D010569:Perylene; C000609392:GCLC protein, human; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione
keywords: Alternaria alternata; Altertoxin I (ATX I); Altertoxin II (ATX II); Confocal/SIM microscopy; Glutathione; Nrf2