RESUMEN
This work presents the synthesis and characterization of eight copper complexes [Cu(L-dipeptide)(neo)]·nH2O (neo = neocuproine) and their cytotoxic activities against tumor cell lines. The crystalline structure of [Cu(gly-val)(neo)]·3H2O, [Cu(gly-leu)(neo)]·H2O, [Cu(ala-gly)(neo)]·4H2O, [Cu(val-phe)(neo)]·4.5H2O and [Cu(phe-phe)(neo)]·3H2O were determined by single crystal X-ray diffraction. In all of them, the Cu(II) is pentacoordinated, in a square pyramidal environment. The coordination observed in solid state was retained in the major species in aqueous solution, as suggested by Electronic Paramagnet Resonance and UV-vis spectroscopies. The complexes were shown to have affinity for isolated DNA, as determined by Circular Dichroism experiments. Furthermore, biological experiments showed that all the complexes present high cytotoxic activity against the cell lines: MDA-MB-231, MCF-7 (human metastatic breast adenocarcinomas, the first triple negative), MCF-10A (human normal breast cells), A549 (human lung epithelial carcinoma) and MRC-5 (human lung epithelial cells). Together, these results suggest that these compounds are promising steps towards new effective drugs to treat cancer.
Asunto(s)
Antineoplásicos/síntesis química , Quelantes/síntesis química , Complejos de Coordinación/síntesis química , Cobre/química , Dipéptidos/química , Fenantrolinas/química , Células A549 , Antineoplásicos/toxicidad , Proliferación Celular/efectos de los fármacos , Quelantes/toxicidad , Complejos de Coordinación/toxicidad , ADN/química , Humanos , Células MCF-7 , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
The present study evaluates the superoxide dismutase (SOD) and catalase (CAT) activities in a wild strain of Drosophila melanogaster and the genotoxic potential induced by Cas II-gly (a new antineoplastic drug) using the somatic mutation and recombination test. Larvae 48h old were treated with Cas II-gly in a range of 0-1.5mM and aliquot were taken every 24h to have individuals treated for 24, 48, 72h and adulthood as well. A dose-dependent toxicity and a significant increase in SOD and CAT activities were found after a 24 and 48h treatment with 0.5-1.5mM concentrations. The comparison of the effect in enzymes with mutation indicated a positive correlation with increased genetic damage, after 24 and 48h of exposure for all concentrations tested. The addition of the genetic damage induced in each exposure time showed a significant effect, but only the small single spots had a concentration-related increase.
Asunto(s)
Antineoplásicos/toxicidad , Quelantes/toxicidad , Cobre/metabolismo , Mutágenos/toxicidad , Compuestos Organometálicos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Animales , Catalasa/metabolismo , Relación Dosis-Respuesta a Droga , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Femenino , Dosificación Letal Mediana , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/genética , Masculino , Estrés Oxidativo/genética , Recombinación Genética/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Alas de Animales/efectos de los fármacosRESUMEN
The aim of this study was to evaluate the effect of Gd-chelate on renal function, iron parameters and oxidative stress in rats with CRF and a possible protective effect of the antioxidant N-Acetylcysteine (NAC). Male Wistar rats were submitted to 5/6 nephrectomy (Nx) to induced CRF. An ionic-cyclic Gd (Gadoterate Meglumine) was administrated (1.5 mM/KgBW, intravenously) 21 days after Nx. Clearance studies were performed in 4 groups of anesthetized animals 48 hours following Gd- chelate administration: 1--Nx (nâ=â7); 2--Nx+NAC (nâ=â6); 3--Nx+Gd (nâ=â7); 4--Nx+NAC+Gd (4.8 g/L in drinking water), initiated 2 days before Gd-chelate administration and maintained during 4 days (nâ=â6). This group was compared with a control. We measured glomerular filtration rate, GFR (inulin clearance, ml/min/kg BW), proteinuria (mg/24 hs), serum iron (µg/dL); serum ferritin (ng/mL); transferrin saturation (%), TIBC (µg/dL) and TBARS (nmles/ml). Normal rats treated with the same dose of Gd-chelate presented similar GFR and proteinuria when compared with normal controls, indicating that at this dose Gd-chelate is not nephrotoxic to normal rats. Gd-chelate administration to Nx-rats results in a decrease of GFR and increased proteinuria associated with a decrease in TIBC, elevation of ferritin serum levels, transferrin oversaturation and plasmatic TBARS compared with Nx-rats. The prophylactic treatment with NAC reversed the decrease in GFR and the increase in proteinuria and all alterations in iron parameters and TBARS induced by Gd-chelate. NAC administration to Nx rat did not modify the inulin clearance and iron kinetics, indicating that the ameliorating effect of NAC was specific to Gd-chelate. These results suggest that NAC can prevent Gd-chelate nephrotoxicity in patients with chronic renal failure.
Asunto(s)
Acetilcisteína/farmacología , Quelantes/toxicidad , Gadolinio/química , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/fisiopatología , Riñón/efectos de los fármacos , Animales , Quelantes/química , Tasa de Filtración Glomerular , Inulina/farmacocinética , Riñón/metabolismo , Riñón/fisiopatología , Masculino , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Chelation therapy occupies a central place in modern medicine and pharmacology, because continuous studies with laboratory animals and extensive clinical experience demonstrate that acute or chronic intoxications with a variety of metals can be considerable improved by administration of a suitable chelating agent. In this review the chemical characteristics, properties and uses of the most common chelating agents as well as those of some new and very promising agents of this type, are discussed. In the second part of the review the biological and biochemical impact of these agents, as well as their use for the treatment of some selected diseases and disorders, are also analyzed and discussed in detail.
Asunto(s)
Quelantes/química , Quelantes/uso terapéutico , Terapia por Quelación , Animales , Quelantes/metabolismo , Quelantes/toxicidad , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Humanos , Iones/metabolismo , Ligandos , Metales/química , Metales/metabolismo , Metales/envenenamiento , Metales/toxicidadRESUMEN
INTRODUCTION: Endodontic chelators may extrude to apical tissues during instrumentation activating cellular events on periapical tissues. This study assessed in vitro the expression of nitric oxide (NO) concentrations by murine peritoneal macrophages after contact with MTAD (Dentsply/Tulsa, Tulsa, OK), Tetraclean (Ogna Laboratori Farmaceutici, Muggio, Italy), Smear Clear (Sybron Endo, Orange, CA), and EDTA (Biodinâmica, Ibiporã, PR, Brazil). METHODS: Macrophage cells were obtained from Swiss mice after peritoneal lavage. Chelators were diluted in distilled water obtaining 12 concentrations, and MTT assay identified the concentrations, per group, displaying the highest cell viability (analysis of variance, p < 0.01). Selected concentrations were tested for NO expression using Griess reaction. Culture medium and lipopolysaccharide (LPS) were used as controls. RESULTS: Analysis of variance and Tukey tests showed that all chelators displayed elevated NO concentrations compared with the negative control (p < 0.01). MTAD induced the lowest NO expression, followed by Tetraclean, EDTA, and Smear Clear. No difference was observed between MTAD and Tetraclean (p > 0.01), Tetraclean and EDTA (p > 0.01), and EDTA and Smear Clear (p > 0.01). LPS ranked similar to both EDTA and Smear Clear (p > 0.01). CONCLUSION: The tested endodontic chelators displayed severe proinflammatory effects on murine-cultured macrophages. Citric acid-based solutions induce lower NO release than EDTA-based irrigants.
Asunto(s)
Quelantes/toxicidad , Macrófagos Peritoneales/efectos de los fármacos , Óxido Nítrico/biosíntesis , Irrigantes del Conducto Radicular/toxicidad , Animales , Células Cultivadas , Ácido Cítrico/toxicidad , Ácido Edético/toxicidad , Mediadores de Inflamación/metabolismo , Macrófagos Peritoneales/metabolismo , RatonesRESUMEN
Chromium poses a potential threat to coastal ecosystems. We used standard toxicity bioassays (semi-static, chronic) to evaluate EDTA as a chelating agent for reducing trivalent and hexavalent chromium toxicity on Petrolisthes laevigatus. Crab survival decreased linearly with increased chromium concentrations and dropped significantly beginning at 40 mg/L Cr (VI) and 80 mg/L Cr (III). No significant differences were observed with Cr (III) + EDTA as compared with untreated controls. Cr (VI) toxicity was greater than that of Cr (III), with low individual survival rates. The protective effect of EDTA in the medium increased crab survival by 41%-48%.
Asunto(s)
Braquiuros , Quelantes/toxicidad , Compuestos de Cromo/toxicidad , Ácido Edético/toxicidad , Restauración y Remediación Ambiental/métodos , Contaminantes Químicos del Agua/toxicidad , Animales , Bioensayo , Chile , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Interacciones Farmacológicas , Longevidad/efectos de los fármacos , Nitratos/toxicidad , Dicromato de Potasio/toxicidad , Agua de Mar , Pruebas de ToxicidadRESUMEN
In the present study, we investigated if thiol-reducing agents are capable of altering mercury (Hg2+), lead (Pb2+) and cadmium (Cd2+) effects on platelet glutamatergic system. Dimercaprol (BAL), a dithiol chelating agent therapeutically used for the treatment of heavy metals poisoning, was capable of protecting the [3H]-glutamate binding against the effects caused by Pb2+ and Hg2+. 2,3-Dimercaptopropane-1-sulfonic acid (DMPS), another dithiol-reducing chelating agent, was capable of protecting the effect caused by Cd2+, Pb2+ and Hg2+. The similar effect was observed with addition of dithiothreitol (DTT) on [3H]-glutamate binding in human platelets. Dithiol-reducing agents (BAL, DMPS and DTT) alone did not alter [3H]-glutamate binding. In contrast, reduced glutathione (GSH), a monothiol-reducing agent, caused a significant inhibition on [3H]-glutamate binding at all concentrations tested. GSH did not modify heavy metal effects on [3H]-glutamate binding in platelets. The findings of the present investigation indicate that dithiol-reducing agents are capable of altering Hg2+, Pb2+ and Cd2+ effects on platelet glutamatergic system. In vitro data on chelating-metal interactions provide only an estimated guide to the treatment of heavy metal poisoning. Consequently, more studies in intoxicated patients are necessary to determine the precise use of the peripheral models and chelating agents.
Asunto(s)
Plaquetas/metabolismo , Ácido Glutámico/metabolismo , Metales Pesados/antagonistas & inhibidores , Metales Pesados/toxicidad , Sustancias Reductoras/farmacología , Compuestos de Sulfhidrilo/farmacología , Adulto , Plaquetas/efectos de los fármacos , Cadmio/antagonistas & inhibidores , Cadmio/toxicidad , Quelantes/toxicidad , Dimercaprol/farmacología , Ditiotreitol/farmacología , Femenino , Humanos , Técnicas In Vitro , Plomo/toxicidad , Masculino , Mercurio/antagonistas & inhibidores , Mercurio/toxicidad , Unitiol/toxicidadRESUMEN
The aim of the present study was to evaluate the interaction between a classic GABAergic antagonist -- pentylenetetrazol (PTZ) with an organoselenium compound -- diphenyl diselenide (PhSe)(2) and with the metal chelating agent -- 2,3 dimercaptopropanol (BAL). Mice were pre-treated with 150 micromol/kg (PhSe)(2) or BAL (250, 500 or 1000 micromol/kg) before treatment with PTZ. Pre-treatment with (PhSe)(2) reduced the latency for PTZ-induced seizure at doses of 40 and 60 mg/kg and cause a decrease in the latency for PTZ-induced death at the dose of 60 mg/kg. However, treatment with PTZ at dose of 80 mg/kg was not affected by (PhSe)(2) pre-treatment. Pre-treatment with BAL reduced the latency for PTZ-induced seizure at doses of 40 and 50 mg/kg. In addition, the latency for PTZ-induced death at the dose of 40 mg/kg was decreased significantly by pre-treatment with all doses of BAL. At the dose of 50mg/kg, a significant decrease in the latency for death occurred only in mice pre-treated with 500 and 1000 micromol/kg of BAL. Our results indicate that the PTZ-induced chemical seizures and mortality was enhanced by (PhSe)(2) and BAL. These results indicated that (PhSe)(2) and BAL interact with PTZ possibly by modulating the GABAergic system.
Asunto(s)
Derivados del Benceno/toxicidad , Convulsivantes/toxicidad , Dimercaprol/toxicidad , Compuestos de Organoselenio/toxicidad , Pentilenotetrazol/toxicidad , Convulsiones/inducido químicamente , Ácido gamma-Aminobutírico/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatología , Quelantes/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Antagonistas del GABA/toxicidad , Masculino , Ratones , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiología , Receptores de GABA/efectos de los fármacos , Receptores de GABA/metabolismo , Convulsiones/metabolismo , Convulsiones/fisiopatología , Tasa de Supervivencia , Factores de TiempoRESUMEN
Solutions of EDTA and citric acid have been used as canal irrigants. These substances must be compatible with apical periodontal tissue. The aim of this study was to evaluate comparatively the cytotoxicity of a 17% EDTA solution and that of three solutions with different concentrations of citric acid (10, 15, and 25%) on cultured fibroblasts. The solutions were diluted to 0.1% and 0.5% in culture medium and then applied to NIH 3T3 cells. After 0, 6, 12, and 24 h (short-term assay; viability) and 1, 3, 5, and 7 days (long-term assay; survival), the cells were counted. The data were compared by ANOVA. In the short-term experiments, all solutions presented a percentage of cell viability similar to that of control cells, except for the 17% EDTA solution diluted to 0.5%. After the long-term assay, all groups presented a continuous and progressive cell growth except for the 17% EDTA solution and for the 25% citric acid solution at a 0.5% dilution. The citric acid solution did not impair cell growth and viability, proving to be noncytotoxic in vitro.
Asunto(s)
Fibroblastos/efectos de los fármacos , Irrigantes del Conducto Radicular/toxicidad , Células 3T3 , Análisis de Varianza , Animales , Supervivencia Celular/efectos de los fármacos , Quelantes/toxicidad , Ácido Cítrico/toxicidad , Ácido Edético/toxicidad , RatonesRESUMEN
This in vivo study evaluated, through the physicochemical assay method for quantification of enhanced vascular permeability, the irritating potential of EDTA, EGTA, citric acid and saline. Thirty-two male Wister rats were anesthetized and four experimental sites were demarcated on their backs. Injections of 2% Evans blue (20 mg/kg) were administered intravenously into the lateral caudal vein. The test solutions were immediately injected intradermally (0.01 mL) into the experimental sites. The animals were killed 30 min, 1, 3 and 6 h after injection of the solutions and each piece of skin was submerged in formamide and incubated at 45 masculineC for 72 h. After filtration, the optical density was measured in a spectrophotometer and the total amount of dye extracted from the samples was calculated by means of a standard calibration curve. Data were analyzed statistically by two-way ANOVA and Tukey's HSD test. Compared to control, EDTA had the greatest volume of dye followed by EGTA and citric acid, for all time periods. There were statistically significant differences between all solutions (p<0.01). Considering the periods assessed, a significant difference was observed between the 3- and 6-h groups (p<0.05), but not between the 30-min and 1-h groups. Among the organic acids evaluated in this study, citric acid yielded the lowest amount of extracted dye. This indicates that the citric acid was the least irritating solution.
Asunto(s)
Permeabilidad Capilar/efectos de los fármacos , Quelantes/toxicidad , Ácido Cítrico/toxicidad , Ácido Edético/toxicidad , Ácido Egtácico/toxicidad , Irrigantes del Conducto Radicular/toxicidad , Animales , Materiales Biocompatibles/toxicidad , Colorantes , Azul de Evans , Inflamación/inducido químicamente , Masculino , Ratas , Ratas Wistar , Cloruro de Sodio/toxicidadRESUMEN
Este estudo in vivo avaliou o potencial irritativo do EDTA, EGTA, ácido cítrico e soro fisiológico (controle) durante a fase exsudativa do processo inflamatório. Aplicou-se, intravenosamente na veia caudal lateral de 32 ratos machos da linhagem "Wistar", variação albina, 20 mg/kg de azul de Evans 2%. Em seguida, no tecido subcutâneo da região dorsal dos animais injetou-se 0,01 mL das soluções testes. Após os intervalos de ½, 1, 3 e 6 horas, os animais foram sacrificados, suas peles dorsais foram excisadas e submetidas à análise do corante extravasado pela espectrofotometria de absorção de luz. Os dados obtidos foram avaliados pela análise de variância a 2 critérios e teste de Tukey. Em todos os períodos de tempo estudados, os maiores valores de corante extravasado foram observados no grupo do EDTA seguido pelos grupos do EGTA e ácido cítrico, em comparação ao grupo controle. Houve diferença estatisticamente significante entre todas as soluções testadas (p<0.01). Quando considerado o fator tempo, notou-se diferença significante entre os grupos de 3 e 6 horas (p<0.05). Entretanto, não houve diferença entre os grupos de tempo de ½ e 1 hora. Dentre os ácidos orgânicos avaliados, os resultados demonstraram que o ácido cítrico apresentou o menor potencial irritativo.
Asunto(s)
Animales , Masculino , Ratas , Permeabilidad Capilar/efectos de los fármacos , Quelantes/toxicidad , Ácido Cítrico/toxicidad , Ácido Edético/toxicidad , Ácido Egtácico/toxicidad , Irrigantes del Conducto Radicular/toxicidad , Materiales Biocompatibles/toxicidad , Colorantes , Azul de Evans , Inflamación/inducido químicamente , Ratas Wistar , Cloruro de Sodio/toxicidadRESUMEN
The therapeutic use of BAL (2,3-dimercaptopropanol) as treatment for poisoning has been halted by data suggesting serious neurotoxicity. This article is a report on the effects of BAL and other dithiols, DMSA (meso-2,3-dimercaptosuccinic acid) and DMPS (2,3-dimercaptopropane-1-sulfonic acid), on [3H]glutamate release and uptake by rat brain synaptosomes and [3H]glutamate uptake by synaptic vesicles. BAL (100 microM) inhibited glutamate uptake (30%) and stimulated its basal release (30%) in synaptosomes, without affecting K+-stimulated release. BAL also inhibited glutamate uptake by synaptic vesicles (up to 60%). DMPS and DMSA (100 microM) had no significant effects on these parameters. The data reported here provide some evidence of glutamate involvement in BAL-induced neurotoxicity by demonstrating direct effects of BAL on glutamatergic system modulation.