Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum.
Leishmaniasis is a neglected tropical disease caused by >20 species of the protozoan parasiteLeishmaniaMeglumine antimoniate (Glucantime) is the first-choice drug recommended by the World Health Organization for the treatment of all types of leishmaniasis. However, the mechanisms of action and toxicity of pentavalent antimonials, including genotoxic effects, remain unclear. Therefore, the mechanism by which meglumine antimoniate causes DNA damage was investigated for BALB/c mice infected byLeishmania(Leishmania)infantumand treated with meglumine antimoniate (20 mg/kg for 20 days). DNA damage was analyzed by a comet assay using mouse leukocytes. Furthermore, comet assays were followed by treatment with formamidopyrimidine-DNA glycosylase and endonuclease III, which remove oxidized DNA bases. In addition, the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in the animals' sera were assessed. To investigate mutagenicity, we carried out a micronucleus test. Our data demonstrate that meglumine antimoniate, as well asL. infantuminfection, induces DNA damage in mammalian cells by the oxidation of nitrogenous bases. Additionally, the antileishmanial increased the frequency of micronucleated cells, confirming its mutagenic potential. According to our data, both meglumine antimoniate treatment andL. infantuminfection promote oxidative stress-derived DNA damage, which promotes overactivation of the SOD-CAT axis, whereas the SOD-GPx axis is inhibited as a probable consequence of glutathione (GSH) depletion. Finally, our data enable us to suggest that a meglumine antimoniate regimen, as recommended by the World Health Organization, would compromise GPx activity, leading to the saturation of antioxidant defense systems that use thiol groups, and might be harmful to patients under treatment.
Laboratório de Genética e Biologia Molecular, Departamento de Biologia, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.|Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Vanessa Ribeiro
VR
Moreira
Laboratório de Genética e Biologia Molecular, Departamento de Biologia, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Luís Cláudio Lima
LCL
de Jesus
Laboratório de Genética e Biologia Molecular, Departamento de Biologia, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.|Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Rossy-Eric Pereira
RP
Soares
Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Luis Douglas Miranda
LDM
Silva
Programa de Pós-graduação em Ciências da Saúde, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.|Laboratório de Fisiologia Experimental, Departamento de Ciências Fisiológicas, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Bruno Araújo Serra
BAS
Pinto
Departamento de Parasitologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil.
Maria Norma
MN
Melo
Laboratório de Fisiologia Experimental, Departamento de Ciências Fisiológicas, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil.
Antonio Marcus de Andrade
AMA
Paes
Laboratório de Genética e Biologia Molecular, Departamento de Biologia, Universidade Federal do Maranhão, São Luís, Maranhão, Brazil silma.pereira@ufma.br.
Silma Regina Ferreira
SRF
Pereira
D000818:Animals; D000981:Antiprotozoal Agents / Q000627:therapeutic use*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D018314:Leishmania infantum / Q000187:drug effects / Q000472:pathogenicity*; D007896:Leishmaniasis / Q000188:drug therapy* / Q000235:genetics*; D008536:Meglumine / Q000627:therapeutic use*; D000077485:Meglumine Antimoniate; D051379:Mice; D008807:Mice, Inbred BALB C; D009942:Organometallic Compounds / Q000627:therapeutic use*
D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D008536:Meglumine; D000077485:Meglumine Antimoniate
antileishmanial; antimony; antioxidant enzymes; genotoxicity; mutagenicity