Genotoxic effects of the antileishmanial drug glucantime super(+)

Leishmaniasis is caused by species of the protozoan parasite Leishmania. It is the third most important vector-borne disease and is widely distributed throughout the world. The World Health Organization recommends pentavalent antimonials as drugs of first choice in its treatment. Although Glucantime super(+) has traditionally been used to treat leishmaniasis, there are still many questions about its structure, mechanisms of action and ability to induce damage in DNA. In this study, the genotoxic activity of this drug was evaluated in vitro using human lymphocytes treated for 3 and 24h (comet assay) and 48h (apoptosis assay) with 3.25, 7.5 and 15mg/ml of Glucantime super(+), respectively, corresponding to 1.06, 2.12 and 4.25mg/ml of pentavalent antimony. In the in vivo tests, Swiss mice received acute treatment with three doses (212.5, 425 and 850mg/kg) of pentavalent antimony. All the treatments were administered intraperitoneally in the volumes of 0.1ml/10g of body weight, adapting human exposure to murine conditions. The animals were treated for 3h in the comet assay using resident peritoneal exudate macrophages, for 24h in the comet assay using peripheral blood leukocytes and for 24h in the bone marrow erythrocyte micronucleus test. While no genotoxic effect was observed in the in vitro tests, the in vivo tests showed that Glucantime super(+) induces DNA damage. These findings indicate that Glucantime super(+) is a pro-mutagenic compound that causes damage to DNA after reduction of pentavalent antimony (SbV) into the more toxic trivalent antimony (SbIII) in the antimonial drug meglumine antimoniate.