| Description: |
Alternariol, a mycotoxin, is found in food and beverages infected by Alternaria alternata, it shows estrogenic potential, inhibition of cell proliferation and clastogenicity in Ishikawa and V79 cells in vitro. Alternariol is also a new phototoxic, DNA-intercalating agent and is a DNA cross-linking mycotoxin in near UV light. Alternariol possesses genotoxic properties, it is a poison of topoisomerase I and II with a certain selectivity for the II isoform. |
| In vitro: |
| Food Chem Toxicol. 2006 Mar;44(3):398-408. | | Estrogenic and clastogenic potential of the mycotoxin alternariol in cultured mammalian cells.[Pubmed: 16194592 ] | The mycotoxin Alternariol (AOH) is found in food and beverages infected by Alternaria alternata. Because consumption of foodstuffs contaminated with A. alternata has been implicated in an elevated incidence of esophageal carcinogenesis, we have investigated the estrogenic potential, the effect on cell proliferation, and the genotoxic effect of AOH in cultured mammalian cells.
METHODS AND RESULTS:
AOH replaced E2 from isolated human estrogen receptors alpha and beta and increased the level of alkaline phosphatase (ALP) mRNA and the enzymatic activity of ALP in a human endometrial adenocarcinoma cell line (Ishikawa cells). The estrogenicity of AOH was about 0.01% of that of E2. The effects in Ishikawa cells were reversed by the ER antagonist ICI 182,780. Analysis of cell proliferation by flow cytometry and microscopy of Ishikawa and Chinese hamster V79 cells revealed that AOH inhibited cell proliferation by interference with the cell cycle. The genotoxic potential was assessed by the micronucleus (MN) assay and immunochemical differentiation between MN containing whole chromosomes (kinetochore-positive) and DNA fragments (kinetochore-negative) in Ishikawa and V79 cells.
CONCLUSIONS:
AOH induced kinetochore-negative MN in both cell lines. This is the first report on the estrogenic potential, inhibition of cell proliferation and clastogenicity of AOH in Ishikawa and V79 cells in vitro. | | Mol Nutr Food Res. 2009 Apr;53(4):441-51. | | Alternariol acts as a topoisomerase poison, preferentially affecting the IIalpha isoform.[Pubmed: 18727009 ] | Alternariol (AOH), a mycotoxin formed by Alternaria alternata, has been reported to possess genotoxic properties. However, the underlying mechanism of action is unclear.
METHODS AND RESULTS:
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.
CONCLUSIONS:
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. |
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