Impact of Alternaria toxins on CYP1A1 expression in different human tumor cells and relevance for genotoxicity. Issue 1 (5th January 2016)

• Record Type: Journal Article
• Authors: Pahlke, G.; Tiessen, C.; Domnanich, K.; Kahle, N.; Groh, I.A.M.; Schreck, I.; Weiss, C.; Marko, D.
• Is Part Of: Toxicology letters. Volume 240:Issue 1(2016)
• Page Start: 93
• Page End: 104
• Publication Date: 2016-01-05
• Subjects: AhR aryl hydrocarbon receptor -- AME alternariol monomethyl ether -- AOH alternariol -- ATX-II altertoxin II -- B[a]P benzo[a]pyrene -- cRNA control siRNA -- CYP1A cytochrome P450 1A -- DCF dichlorofluorescein -- DCFH-DA dichloro-dihydro-fluorescein diacetate -- DMSO dimethlysulfoxid -- EROD ethoxyresorufin O-deethylase -- MEN menadione -- ROS reactive oxygen species -- siRNA small interfering ribonucleotide acid -- SRB sulforhodamine B -- WST-1 stable tetrazolium salt; Alternariol -- Alternariol monomethyl ether -- Altertoxin-II -- CYP1A -- Aryl hydrocarbon receptor -- Genotoxicity; Toxicology -- Periodicals; 363.179
• DOI: 10.1016/j.toxlet.2015.10.003
• Languages: English
• ISSNs: 0378-4274

Abstract

Highlights: CYP1A induction by alternariol is AhR-dependent. CYP1A induction by alternariol has no substantial impact on genotoxicity. ATX-II acts as an inducer of CYP1A expression. 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.