Alternariol acts as a topoisomerase poison, preferentially affecting the IIα isoform

Fehr, Markus; Pahlke, Gudrun; Fritz, Jessica; Christensen, Morten O.; Boege, Fritz; Altemöller, Martina; Podlech, Joachim; Marko, Doris

doi:10.1002/mnfr.200700379

Cited by 181 publications

(179 citation statements)

References 31 publications

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“…AOH has been recently characterised as an inhibitor of DNA topoisomerase I and II with a certain selectivity for the II alpha isoform (Fehr et al, 2009). DNA topoisomerases are enzymes responsible for regulation of genomic DNA supercoiling and participate in essential processes of cells such as replication, transcription, recombination, repair, etc.…”

Section: Mechanism Of Genotoxicitymentioning

confidence: 99%

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

2011

EFSA Journal

400

188

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The European Commission asked the European Food Safety Authority to review the safety of Alternaria toxins in food and feed. In addition to causing plant diseases on many crops such as cereals, oilseeds, tomatoes, apples and olives, some of these toxins are genotoxic in vitro and/or fetotoxic in rats. This opinion deals with alternariol, alternariol monomethyl ether, tenuazonic acid, iso-tenuazonic acid, altertoxins, tentoxin, altenuene and AAL-toxins (Alternaria alternata f. sp. lycopersici toxins). Two Member States provided 11,730 occurrence results in food and also data published in the scientific literature were considered. Generally these toxins were found in grains and grain-based products, tomato and tomato products, sunflower seeds and sunflower oil, fruits and fruit products, and beer and wine. The feed occurrence data (1150 results) were collected from the literature only. The knowledge on toxic effects of Alternaria toxins on farm and companion animals and occurrence data in feed were insufficient to assess the health risk for different species. For chicken there are indications that alternariol represents a health risk but it cannot be excluded that tenuazonic acid could also be of concern. Considering: (1) there are few or no relevant toxicity data on Alternaria toxins, (2) the chemical structure of several of them is known, (3) dietary exposure data exist for some of them, the Panel on Contaminants in the food chain used the threshold of toxicological concern (TTC) approach to assess the relative level of concern for dietary exposure of humans to these mycotoxins. For the genotoxic Alternaria toxins, alternariol and alternariol monomethyl ether, the estimated chronic dietary exposure exceeded the relevant TTC value indicating a need for additional toxicity data. The dietary exposure estimates for nongenotoxic tentoxin and tenuazonic acid are lower than the relevant TTC value and are considered unlikely to be a human health concern. SUMMARYAlternaria toxins are mycotoxins produced by Alternaria species that cause plant diseases on many crops. They are the principal contaminating fungi in wheat, sorghum and barley, and have also been reported to occur in oilseeds such as sunflower and rapeseed, tomato, apples, citrus fruits, olives and several other fruits and vegetables. Alternaria alternata is the most common Alternaria species in harvested fruits and vegetables, and is the most important mycotoxin-producing species. Due to their growth even at low temperature, Alternaria species are also responsible for spoilage of these commodities during refrigerated transport and storage.Alternaria species produce more than 70 phytotoxins, but a small proportion of them have been chemically characterised and reported to act as mycotoxins to humans and animals. Some toxins such as alternariol (AOH), alternariol monomethyl ether (AME), tenuazonic acid (TeA) and altertoxins (ATX) are described to induce harmful effects in animals, including fetotoxic and teratogenic effects. Culture extracts of A. altern...

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Section: Mechanism Of Genotoxicitymentioning

confidence: 99%

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

2011

EFSA Journal

400

188

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“…Recent studies have shown that AOH and AME are able to induce DNA strand breaks, micronuclei and gene mutations in various cultured mammalian cells [5][6][7], and to inhibit topoisomerase I and IIa under cell-free conditions [8]. Moreover, AOH and AME are prone to cytochrome P450 (CYP)-mediated hydroxylation in vitro, leading to catechol and hydroquinone metabolites [9].…”

Section: Introductionmentioning

confidence: 99%

Oxidative metabolism of the mycotoxins alternariol and alternariol‐9‐methyl ether in precision‐cut rat liver slices in vitro

Burkhardt

Wittenauer

Pfeiffer

et al. 2011

Molecular Nutrition Food Res

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“…They have been reported to exhibit cytotoxic, fetotoxic, teratogenic, and possible mutagenic and estrogenic effects (24)(25)(26)(27) and may contribute to development of human esophageal cancer (28). AOH has been demonstrated to inhibit cholinesterase (29) and topoisomerases I and II (30). Furthermore, it was shown that AOH induces DNA damage and cell cycle arrest in vitro in the murine macrophage RAW 264.7 cell line, and the treated cells exhibited an abnormal nuclear morphology (31,32).…”

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confidence: 99%

SnPKS19 Encodes the Polyketide Synthase for Alternariol Mycotoxin Biosynthesis in the Wheat Pathogen Parastagonospora nodorum

Chooi

Muria-Gonzalez

Mead

et al. 2015

Appl Environ Microbiol

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b Alternariol (AOH) is an important mycotoxin from the Alternaria fungi. AOH was detected for the first time in the wheat pathogen Parastagonospora nodorum in a recent study. Here, we exploited reverse genetics to demonstrate that SNOG_15829 (SnPKS19), a close homolog of Penicillium aethiopicum norlichexanthone (NLX) synthase gene gsfA, is required for AOH production. We further validate that SnPKS19 is solely responsible for AOH production by heterologous expression in Aspergillus nidulans. The expression profile of SnPKS19 based on previous P. nodorum microarray data correlated with the presence of AOH in vitro and its absence in planta. Subsequent characterization of the ⌬SnPKS19 mutants showed that SnPKS19 and AOH are not involved in virulence and oxidative stress tolerance. Identification and characterization of the P. nodorum SnPKS19 cast light on a possible alternative AOH synthase gene in Alternaria alternata and allowed us to survey the distribution of AOH synthase genes in other fungal genomes. We further demonstrate that phylogenetic analysis could be used to differentiate between AOH synthases and the closely related NLX synthases. This study provides the basis for studying the genetic regulation of AOH production and for development of molecular diagnostic methods for detecting AOH-producing fungi in the future.

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Alternariol acts as a topoisomerase poison, preferentially affecting the IIα isoform

Cited by 181 publications

References 31 publications

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

Scientific Opinion on the risks for animal and public health related to the presence ofAlternariatoxins in feed and food

Oxidative metabolism of the mycotoxins alternariol and alternariol‐9‐methyl ether in precision‐cut rat liver slices in vitro

SnPKS19 Encodes the Polyketide Synthase for Alternariol Mycotoxin Biosynthesis in the Wheat Pathogen Parastagonospora nodorum

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