Genistein and Ascorbic Acid reduce oxidative stress-derived DNA damage induced by antileishmanial meglumine antimoniate [PublishAheadOfPrint]

Meglumine antimoniate (Glucantime) is an antimonial pentavalent used to treat leishmaniasis, despite its acknowledged toxic effects, such as its ability to cause oxidative damage to lipids and proteins. Recently, our group demonstrated that meglumine antimoniate causes oxidative stress-derived DNA damage. Acknowledging that antioxidants modulate reactive oxygen species, we evaluated the capacity of genistein and ascorbic acid for preventing genotoxicity caused by meglumine antimoniate. For that, mice (n=5/group) received genistein (via gavage) in doses of 5, 10 and 20mg/kg for three consecutive days. After this period, they were treated with 810mg/kg meglumine antimoniate via intraperitoneal (i.p.). Furthermore, mice (n=5/group) received, simultaneously, ascorbic acid (i.p.) in doses of 30, 60 and 120mg/kg and 810mg/kg meglumine antimoniate. We also conducted post- and pre-treatment assays, in which animals received ascorbic acid (60mg/kg) 24 hours prior to or after receiving meglumine antimoniate. Genomic instability and mutagenicity were analyzed through conventional Comet assay and enzymatic assay using Formamidepyrimidine-DNA-glycosylase (Fpg) enzyme, as well as the Micronucleus Test, respectively. Meglumine antimoniate induced an increase in the DNA damage after digestion with Fpg, reinforcing its mutagenic potential by oxidizing DNA bases, which was prevented by genistein. Similarly, ascorbic acid proved itself capable of reducing mutagenic effects in simultaneous treatment, as well as in post-treatment. Therefore, our results demonstrate that both compounds are efficient in preventing mutations in mammalian cells treated with meglumine antimoniate.

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