Increased expression of iron-containing superoxide dismutase-A (TcFeSOD-A) enzyme in Trypanosoma cruzi population with in vitro-induced resistance to benznidazole

Nogueira, Fernanda B.; Krieger, Marco Aurélio; Nirdé, Philippe; Goldenberg, Samuel; Romanha, Álvaro J.; Murta, Silvane Maria Fonseca

doi:10.1016/j.actatropica.2006.10.004

Cited by 54 publications

(79 citation statements)

References 44 publications

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“…Similar analyses of other trypanosomal superoxide dismutase isoforms through a loss of function or overexpression yielded recombinant cells that displayed a benznidazole sensitivity equivalent to that of controls, suggesting that superoxide production does not occur at appre-ciable levels in other cellular locations (52). These findings appear to be at odds with studies that showed that T. cruzi parasites selected for benznidazole resistance have elevated levels of mitochondrial superoxide dismutase activity (30). However, cells selected for drug resistance also display altered expressions of several additional enzymes, including other components of the parasite's oxidative defense system, which may explain this discrepancy (28).…”

contrasting

confidence: 54%

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

Hall

Wilkinson

2012

Antimicrob Agents Chemother

190

180

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Benznidazole, a 2-nitroimidazole, is the front-line treatment used against American trypanosomiasis, a parasitic infection caused by Trypanosoma cruzi. Despite nearly 40 years of use, the trypanocidal activity of this prodrug is not fully understood. It has been proposed that benznidazole activation leads to the formation of reductive metabolites that can cause a series of deleterious effects, including DNA damage and thiol depletion. Here, we show that the key step in benznidazole activation involves an NADH-dependent trypanosomal type I nitroreductase. This catalyzes an oxygen-insensitive reaction with the interaction of enzyme, reductant, and prodrug occurring through a ping-pong mechanism. Liquid chromatography/mass spectrometry (LC/MS) analysis of the resultant metabolites identified 4,5-dihydro-4,5-dihydroxyimidazole as the major product of a reductive pathway proceeding through hydroxylamine and hydroxy intermediates. The breakdown of this product released the reactive dialdehyde glyoxal, which, in the presence of guanosine, generated guanosine-glyoxal adducts. These experiments indicate that the reduction of benznidazole by type I nitroreductase activity leads to the formation of highly reactive metabolites and that the expression of this enzyme is key to the trypanocidal properties displayed by the prodrug.

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contrasting

confidence: 54%

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

Hall

Wilkinson

2012

Antimicrob Agents Chemother

190

180

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“…En este sentido, al ser justo las cepas más resistentes, aisladas de aquellas regiones donde posiblemente no se ha suministrado el tratamiento, se infiere que las cepas colombianas de T. cruzi podrían poseer resistencia natural al benzonidazol que no depende del uso de los medicamentos, que pueden generar procesos de inducción de resistencia. Por lo tanto, sugerimosEn la actualidad, diversos autores han tratado de correlacionar los mecanismos de resistencia natural con los de resistencia inducida (16)(17)(18)(19)(20)(21). Sin embargo, hasta el momento no se han encontrado patrones de expresión similares en cepas que presentan los dos tipos de resistencia, lo que ha llevado a concluir que diferentes mecanismos actúan en ambos tipos de resistencia.…”

Section: Discussionunclassified

“…Además, se reportó que es posible inducir resistencia en este parásito, tanto in vitro como in vivo, por presiones continuas con estos medicamentos (12)(13)(14)(15), lo cual genera poblaciones resistentes a concentraciones de benzonidazol de hasta 220 μM (15), y se han propuesto algunos genes involucrados en el surgimiento del fenotipo de resistencia a este medicamento (12,13,(16)(17)(18)(19)(20)(21). A la fecha, no se han podido correlacionar los mecanismos moleculares involucrados entre estos dos tipos de resistencia (16)(17)(18)(19)(20)(21), ni tampoco la resistencia con otros parámetros biológicos, genéticos o bioquímicos de T. cruzi (22,23).…”

Section: Sensibilidad Al Benzonidazol De Trypanosoma Cruziunclassified

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

Mejía-Jaramillo¹,

Fernández²,

Montilla³

et al. 2012

biomedica

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Introducción. La enfermedad de Chagas, causada por Trypanosoma cruzi, es uno de los problemas más graves de salud pública en el continente americano. El benzonidazol es uno de los dos medicamentos utilizados para tratar la enfermedad de Chagas. Sin embargo, la variación de la sensibilidad del parásito a este medicamento es una de las principales causas del fracaso del tratamiento. Objetivo. Evaluar la sensibilidad in vitro al benzonidazol de cepas colombianas de T. cruzi de diferentes orígenes y procedencia geográfica. Materiales y métodos. Treinta y tres cepas colombianas de T. cruzi aisladas de humanos, vectores y mamíferos, se analizaron in vitro mediante el micrométodo enzimático de MTT para determinar la concentración inhibitoria 50 (CI 50 ) al benzonidazol. Se estudió la correlación entre la sensibilidad in vitro al medicamento y diferentes parámetros biológicos y eco-epidemiológicos. Resultados. El análisis de sensibilidad al medicamento indicó que el 36 % de las cepas eran sensibles, el 48 %, parcialmente resistentes y, el 16 %, resistentes al benzonidazol. Los análisis de correlación entre las CI 50 con algunos parámetros biológicos y eco-epidemiológicos, mostraron diferencias en cuanto a la sensibilidad según el origen biológico y el área geográfica de procedencia de la cepa. Conclusiones. Existe una gran variabilidad en cuanto a la sensibilidad al benzonidazol de las cepas circulantes de T. cruzi en Colombia, lo cual sugiere la presencia de cepas naturalmente resistentes en el país. Palabras clave:Trypanosoma cruzi, enfermedad de Chagas/terapia, inmunidad innata, Colombia. Trypanosoma cruzi strains resistant to benznidazole occurring in ColombiaIntroduction. Chagas disease caused by Trypanosoma cruzi is one of the most serious public health problems in the Americas. Benznidazole is one of two drugs used to treat Chagas' disease. However, the variation in susceptibility of the parasite to this drug is one of the main causes of treatment failure. Objective. The in vitro susceptibility to benznidazole was assessed in Colombian strains of T. cruzi from several sources and geographical regions. Materials and methods. Thirty-three Colombian T. cruzi strains were isolated from humans, vectors and mammals. These were analyzed in vitro by the MTT enzymatic micromethod to determine the IC 50 to benznidazole. Additionally, the in vitro susceptibility was correlated with several biological and ecoepidemiological parameters. Results. Thirty-six percent of the strains were considered to be sensitive, 48% partially resistant, and 16% were resistant. Correlations between the IC 50 and several biological and eco-epidemiological parameters indicated that differences in susceptibility depended on the biological source and geographical origin of the strain. Conclusions. A high degree of variability exists in the susceptibility to benznidazole of T. cruzi strains in Colombia. The distribution data indicate the presence and circulation of naturally resistant strains.

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“…Destes, a DEC (Hetrazan ®) é a droga mais antiga e o fármaco [58]. A doença é causada pelo protozoário parasita Trypanosoma cruzi e foi descoberta há mais 100 anos [59]. É uma das mais sérias doenças parasitárias na América Latina.…”

Section: Dietilcarbamazina E Citrato De Dietilcarbamazinaunclassified

“…The O34-C37-C38-N41 chain of atoms linking the phenyl group to the terminal ring assumes, as in PIDXIJ, a gauche conformation, the torsion angles being 67.5 (2) and 59 , respectively. The bond lengths and angles of the chain show differences when comparing both structures.…”

Section: Commentmentioning

confidence: 99%

Caracterização no estado sólido de insumos farmacêuticos ativos: planejamento racional de novas formas cristalinas.

Ellena¹

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Increased expression of iron-containing superoxide dismutase-A (TcFeSOD-A) enzyme in Trypanosoma cruzi population with in vitro-induced resistance to benznidazole

Cited by 54 publications

References 44 publications

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

Activation of Benznidazole by Trypanosomal Type I Nitroreductases Results in Glyoxal Formation

Sensibilidad al benzonidazol de cepas de Trypanosoma cruzi sugiere la circulación de cepas naturalmente resistentes en Colombia

Caracterização no estado sólido de insumos farmacêuticos ativos: planejamento racional de novas formas cristalinas.

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