title: Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform.
abstract: Alternariol (AOH), a mycotoxin formed by Alternaria alternata, has been reported to possess genotoxic properties. However, the underlying mechanism of action is unclear. Here, we tested the hypothesis that interactions with DNA-topoisomerases play a role in the DNA-damaging properties of AOH. First we compared DNA-damaging properties of AOH with other Alternaria mycotoxins such as AOH monomethyl ether (AME), altenuene and isoaltenuene. AOH and AME significantly increased the rate of DNA strand breaks in human carcinoma cells (HT29, A431) at micromolar concentrations, whereas altenuene and isoaltenuene did not affect DNA integrity up to 100 microM. Next, we selected AOH as the most DNA-damaging Alternaria metabolite for further studies of interactions with DNA topoisomerases. In cell-free assays, AOH potently inhibited DNA relaxation and stimulated DNA cleavage activities of topoisomerase I, IIalpha and IIbeta. Stabilisation of covalent topoisomerase II-DNA intermediates by AOH was also detectable in cell culture, and here, the IIalpha isoform was preferentially targeted. AOH is thus characterised as a poison of topoisomerase I and II with a certain selectivity for the IIalpha isoform. Since topoisomerase poisoning and DNA strand breakage occurred within the same concentration range, poisoning of topoisomerase I and II might at least contribute to the genotoxic properties of AOH.
authors: Institute of Applied Biosciences, Section of Food Toxicology, Universität Karlsruhe (TH), Karlsruhe, Germany.
authors: Markus
authors: M
authors: Fehr
authors: Gudrun
authors: G
authors: Pahlke
authors: Jessica
authors: J
authors: Fritz
authors: Morten O
authors: MO
authors: Christensen
authors: Fritz
authors: F
authors: Boege
authors: Martina
authors: M
authors: Altemöller
authors: Joachim
authors: J
authors: Podlech
authors: Doris
authors: D
authors: Marko
mesh_terms: D000951:Antigens, Neoplasm; D006690:Bisbenzimidazole / Q000378:metabolism; D045744:Cell Line, Tumor; D053960:DNA Breaks; D004250:DNA Topoisomerases, Type II; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004996:Ethidium / Q000378:metabolism; D006801:Humans; D007783:Lactones / Q000633:toxicity*; D009183:Mycotoxins / Q000633:toxicity*; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D007783:Lactones; D009183:Mycotoxins; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II; D004996:Ethidium; C005197:alternariol; D006690:Bisbenzimidazole; C018206:alternariol monomethyl ether