Soy isoflavones have antimutagenic activity on DNA damage induced by the antileishmanial Glucantime (meglumine antimoniate)

Abstract

Isoflavones are phytoestrogens reported to be potent antioxidant agents. In contrast, the antileishmanial meglumine antimoniate has mutagenic activities. This study evaluated the ability of soy isoflavones to reduce DNA damage induced by meglumine antimoniate. Antimutagenic effects (by micronucleus test) were tested using Swiss mice divided into seven groups treated with meglumine antimoniate (425 mg/kg bw pentavalent antimony); cyclophosphamide (50 mg/kg bw); water (negative control); single isoflavones dose (1.6 mg/kg bw), and three groups received one dose of isoflavones via gavage (0.4 mg/kg bw, 0.8 mg/kg bw or 1.6 mg/kg bw) plus meglumine antimoniate via intraperitoneal, simultaneously. To evaluate antigenotoxicity (by Comet assay), each group with 10 animals received the above-mentioned control doses; single dose of isoflavones 0.8 mg/kg bw, and three groups received isoflavones (0.8 mg/kg bw) by gavage along with intraperitoneal meglumine antimoniate, which were treated with isoflavones 24 h before or after receiving meglumine antimoniate (pre-treatment and post-treatment, respectively) or simultaneously. Cells were harvested 24 h after the treatment, and the data were evaluated by ANOVA followed by Tukey's test (p < 0.05). The data from the simultaneous treatment by micronucleus test revealed that isoflavones (0.4 and 0.8 mg/kg) were able to reverse the mutagenic effect of Glucantime. Moreover, all regimes of the treatment with 0.8 mg/kg bw dose were able to reduce the genotoxicity caused by meglumine antimoniate. It is suggested that the protective effect of isoflavones against DNA damage is related to their ability to reduce oxidative stress caused by the trivalent Sb(III) metabolite of meglumine antimoniate.

Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum

“…According to Singh et al (50), high ROS production, such as that observed in the oxidative burst, may lead to saturation of this antioxidant pathway due to the large consumption of GSH by GPx. These observations are in line with our results, especially because it has been shown that Sb III is able to impair the redox balance by promoting intracellular GSH depletion and glutathione reductase inhibition, thereby preventing GSH regeneration (14)(15)(16)(17)(18).…”

“…This result is consistent with the fact that Sb III is a borderline metal ion with a high affinity for nitrogen-and sulfhydryl-containing ligands (25). Our results also support the findings of Cantanhêde et al (18), who showed that soybean isoflavone, a potent antioxidant, was able to reduce the genetic damage caused by meglumine antimoniate.…”

“…More recently, Lima et al (13) described the mutagenic effect of meglumine antimoniate in Swiss mice receiving acute doses of the drug. Additionally, Cantanhêde et al (18) reported the ability of antioxidants to reduce the mutagenic effect of meglumine antimoniate.…”

“…Previously, our group demonstrated the genotoxic effects of meglumine antimoniate on the DNA of uninfected Swiss mice receiving a single dose of the drug (13), as well as the ability of antioxidants to prevent these effects (18). Based on those findings, this study was conducted on BALB/c mice infected with Leishmania (Leishmania) infantum in order to investigate the mechanism by which meglumine antimoniate causes DNA lesions.…”

“…Considering our previous reports that demonstrated the capacity of meglumine antimoniate to induce mutations in vivo (13), the frequency of which was reduced by antioxidant isoflavones (18), in the present study we investigated whether the mutagenic effect of meglumine antimoniate is related to its ability to promote oxidation in DNA nitrogenous bases by oxidative stress.…”