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  • Besides chemopreventive effects against oxidative DNA damage

    2019-11-21

    Besides chemopreventive effects against oxidative DNA damage we evaluated the protective effects of the three Hypericum sp. and isolated compounds against alkylating DNA damage induced by MMS in HT29 cells. Human exposure to alkylating agents, from different sources, occurs in a continuous way and its involvement in cancer initiation has been mentioned in several studies (Povey et al., 2000). Protection against DNA alkylating damage conferred by diet emerges as relevant and a few studies demonstrate its chemopreventive potential. Our results showed that HP, Q, R and Ch are able to protect DNA from AlkD-sensitive sites induced by MMS while HP, HU and Q protected DNA from FPG-sensitive sites induced by MMS. Possible mechanisms involved in DNA protection against alkylating damage could be the transference of alkyl groups to the extracts/compounds, competition by the alkylating site and/or modulation of drug metabolism (Belloir et al., 2006, Franke et al., 2005b, Hamilton et al., 2006). Several other dietary agents namely, red wine polyphenols, resveratrol (Sengottuvelan et al., 2009), Q, R, curcumin, silymarin, lycopene and farnesol, with antioxidant properties, have been found to inhibit induction of colon carcinogenis by alkylating drugs such as 1,2-dimethylhydrazine (DMH) or azoxymethane (AOM) and DNA damage in animal models (Kim et al., 1998, Volate et al., 2005). Orange juice and vitamin C have also shown protective effects against DNA damage induced by MMS (Franke et al., 2005a, Franke et al., 2005b). The enhancement of DNA repair can be understood as a cancer prevention strategy and an important molecular target for dietary phytochemicals. Nevertheless, until now, few studies have investigated the effects of diet on modulation of DNA repair activity in humans. Useful in this regard are new modifications of the comet assay that assess effects of diet on DNA repair ability. These “in vitro repair assays” measure the excision repair activity of a protein extract prepared from dihydrofolate reductase inhibitor antibacterial treated with dietary agents, incubated with a DNA substrate containing a specific type of damage (Collins et al., 2001, Gaivao et al., 2009). In the present study we used a modified “in vitro BER assay” to measure alkylation damage repair activity of cell extracts, through incubation with a DNA substrate containing MMS-induced damage. Here we report for the first time, that HP, HA and Ch has a BER inductive effect, increasing excision activity of a HT29 cell extract on a DNA substrate containing N-alkylating DNA damage compared with a control cell extract (HT29 cells treated with DMSO). No effect on NER activity of cell extracts incubated with Hypericum extracts or isolated compounds, was observed. Stimulation of BER activity by Hypericum extracts and Ch is an important mechanism for chemoprevention of colon cancer. In a previous study we reported that some polyphenols, such as, luteolin, luteolin-7-glucoside and Q increased oxidative repair activity in colon and liver cells (Ramos et al., 2010a, Ramos et al., 2010b, Ramos et al., 2008). Also other studies have investigated the effect of some phytochemicals, such as Q, rosmarinic acid, β-cryptoxantin, β-carotene, lycopene, vitamins E and C as inducers of DNA repair activity (Davis and Milner, 2007, Fillion et al., 1998, Lorenzo et al., 2009, Min and Ebeler, 2009, Ramos et al., 2010a, Ramos et al., 2010b, Ramos et al., 2008). The biological activity of Hypericum extracts should not be exclusively explained based on the effects of the major compound because it may also include the response to other bioactive compounds present in smaller concentrations. Interaction between compounds (synergistic effect) present in the extracts and also to metabolites formed during the metabolism of phytochemicals that could be more active than the original compound can also not be excluded at this point. In conclusion, Hypericum water extracts possess antigenotoxic properties and protect colon cells from oxidative and alkylating DNA damage also increasing alkylating DNA repair activity. The protective effect could be due, in part, to the presence of high amount of phenolic compounds that showed to be also protective. However, other factors, referred previously, should be attended to in future studies. Consumption of herbal teas produced with Hypericum sp, namely Hypericum perforatum, Hypericum androsaeum, and Hypericum undulatum may contribute to colon cancer prevention.