Methyleugenol and oxidative metabolites induce DNA damage and interact with human topoisomerases
Methyleugenol and oxidative metabolites induce DNA damage and interact with human topoisomerases
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DOI：
10.1007/s00204-015-1625-3
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发表时间：
2016-11-01
影响因子：
6.1
通讯作者：
Esselen, Melanie
中科院分区：
文献类型：
--
作者：
Groh, Isabel Anna Maria;Rudakovski, Olga;Esselen, Melanie
甲基丁香酚是一种取代的烯基苯，存在于几种草药和香料中。它被欧盟食品科学委员会归类为具有遗传毒性的致癌物。我们阐述了甲基亮酚及其氧化代谢产物的遗传毒性的生物学机制。甲基丁香酚及其氧化代谢产物可显著增强人结肠癌细胞(HT29)的DNA损伤。甲基丁香酚不影响DNA双链断裂的生物标志物--γ-H_2AX的蛋白状态，而其代谢产物甲基-2‘，3’-环氧化物和3‘-氧甲基异丁香酚显著增加细胞内磷酸化的H_2AX水平。这两种代谢产物在HT29细胞中也显示出明显的微核诱导作用。此外，我们调查了拓扑异构酶的相互作用是否有助于观察到的对DNA完整性的影响。甲基丁香酚-2‘，3’-环氧化物和3‘-氧甲基异丁香酚抑制重组拓扑异构酶I的活性。在HT29细胞中，甲基丁香酚和代谢产物都不影响与DNA结合的拓扑异构酶蛋白的水平，不包括拓扑异构酶中毒的作用方式。此外，3‘-氧甲基异丁香酚还能有效降低喜树碱稳定的拓扑异构酶I/DNA中间体水平和喜树碱诱导的DNA链断裂。综上所述，3‘-氧甲基异丁香酚也可能与经典的或食源性的拓扑异构酶I类毒物相互作用，降低其毒力。
Methyleugenol is a substituted alkenylbenzene found in several herbs and spices. It is classified by the European Union's Scientific Committee on Food as a genotoxic carcinogen. We addressed the biological mechanism of the genotoxic properties of methyleugenol and its oxidative metabolites. Methyleugenol and the oxidative metabolites significantly enhanced the DNA damage in human colon carcinoma cells (HT29). Methyleugenol did not affect the protein status of gamma H2AX, a biomarker of DNA double-strand breaks, whereas its metabolites methyleugenol-2',3'-epoxide and 3'-oxomethylisoeugenol significantly increased the cellular phosphorylated H2AX level. Both of these metabolites also showed a significant induction of micronuclei in HT29 cells. Furthermore, we investigated whether topoisomerase interaction contribute to the observed effect on DNA integrity. Methyleugenol-2',3'-epoxide and 3'-oxomethylisoeugenol inhibited the activity of recombinant topoisomerase I. In HT29 cells, neither methyleugenol nor the metabolites affected the level of topoisomerase protein bound to DNA, excluding a topoisomerase poisoning mode of action. In addition, 3'-oxomethylisoeugenol potently diminished the level of camptothecin-stabilized topoisomerase I/DNA intermediates and camptothecin-induced DNA strand breaks. In conclusion, it could be suggested that 3'-oxomethylisoeugenol may also interact with classical or food-borne topoisomerase I poisons, diminishing their poisoning effectiveness.