Meglumine Antimoniate (Glucantime) Causes Oxidative Stress-Derived DNA Damage in BALB/c Mice Infected by Leishmania (Leishmania) infantum
| Autor: | Luís Cláudio Lima de Jesus, Bruno Araújo Serra Pinto, Luis Douglas Miranda Silva, Maria Norma Melo, Vanessa Ribeiro Moreira, Antonio Marcus de Andrade Paes, Rossy-Eric Pereira Soares, Silma Regina Ferreira Pereira |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
DNA damage Meglumine antimoniate Antiprotozoal Agents Pharmacology medicine.disease_cause Mice 03 medical and health sciences Meglumine Organometallic Compounds medicine Animals Experimental Therapeutics Pharmacology (medical) Leishmania infantum Leishmaniasis chemistry.chemical_classification Mice Inbred BALB C Meglumine Antimoniate biology Glutathione peroxidase Leishmania biology.organism_classification Comet assay 030104 developmental biology Infectious Diseases chemistry Genotoxicity Oxidative stress DNA Damage medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 61 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.02360-16 |
| Popis: | Leishmaniasis is a neglected tropical disease caused by >20 species of the protozoan parasite Leishmania . Meglumine 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 by Leishmania ( Leishmania ) infantum and 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 as L. infantum infection, 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 and L. infantum infection 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. |
| Databáze: | OpenAIRE |
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