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Study of the natural alkenylbenzenes compounds: mechanisms of DNA lesions and implications for humana health
Publication . Martins, Célia Maria da Silva; Rodrigues, António Sebastião; Rueff, José
Alkenylbenzenes are a family of natural compounds found in spices, such as nutmeg, clove and anise, and essential oils of various plants and encompass more than 30 compounds with different structural features. The natural sources containing these compounds have been used not only in foods but in medicines for thousands of years, in essential oils, infusions, teas or even in pharmaceutical formulations. Consequently, this family of natural compounds is present and widely used not only in Western diets but in medicinal preparations, providing a significant potential risk, as some of these compounds have genotoxic properties. In this thesis our goal was to assess the mechanisms of genotoxicity of several alkenylbenzenes, including eugenol, estragole and myristicin, all widely present in spices. We showed that eugenol, present in clove, induced chromosomal aberrations in V79 Chinese hamster cells and H2AX phosphorylation in AA8 Chinese hamster ovary cells, indicating the formation of double-strand breaks. More interestingly eugenol induced endoreduplication, which suggested that this compound is a topoisomerase inhibitor. Another alkenylbenzene studied was estragole, present in tarragon, basil and anise. This compound was shown to produce DNA strand breakage, sister chromatid exchanges and DNA adducts, which could be responsible for its genotoxicity. Our results also indicated that myristicin, an alkenylbenzene present in basil, anise, cinnamon, clove, fennel, nutmeg, parsley and star anise, is not genotoxic but is apoptotic, and downregulates DNA damage response genes, with significant under-expression of genes associated with nucleotide excision repair, double strand break repair and DNA damage signalling and stress response. Finally, as a proof of concept, we addressed DNA methylation alterations in several genes induced by prolonged exposure to a low dose (10 μM) of the alkenylbenzenes eugenol and elemicin in human breast cancer MCF-7 cells. We showed that eugenol and elemicin can increase expression of RASSF1A in MCF-7 breast cancer cells, as measured by RT-PCR, and can induce DNA demethylation, although without a direct clear cut result. Unexpectedly, we also observed an increased in phospho-ATM and phospho-H2AX after prolonged exposure to eugenol and elemicin, indicating possible genotoxic effects at low doses. Globally, our results may contribute to a further understanding of the potential risk of increasing our consumption of these alkenylbenzenes present in the diet, as was recommended by the Joint FAO/WHO Expert Committee on Food Additives (JECFA).
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Fundação para a Ciência e a Tecnologia
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SFRH
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SFRH/BD/81097/2011