Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 390
Filtrar
1.
J Biochem Mol Toxicol ; 33(9): e22366, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31332882

RESUMO

Colchicine (COL) is an alkaloid existing in plants of Liliaceous colchicum. It has widely been used in the treatments of many diseases, such as gout, Familial Mediterranean Fever, and tumor. However, the adverse effects of COL are an obstacle to its safe use. The present studies explored the role of metabolic demethylation in the development of COL-induced hepatotoxicity. We found that inhibition of CYP3A increased the susceptibility of mice to COL hepatotoxicity, and induction of CYP3A decreased the susceptibility of animals to the hepatotoxicity. The toxicokinetic study demonstrated that pretreatment with ketoconazole caused elevated area under the concentration-time curve of COL. Three demethylation metabolites of COL were found to be less hepatotoxic than the parent compound. It appears that the formation of electrophilic demethylation metabolites was not involved in the development of COL-induced liver injury.


Assuntos
Colchicina/farmacocinética , Colchicina/toxicidade , Fígado/efeitos dos fármacos , Animais , Citocromo P-450 CYP3A/metabolismo , Cetoconazol/administração & dosagem , Fígado/metabolismo , Masculino , Metilação , Camundongos
2.
World J Gastroenterol ; 24(44): 5005-5012, 2018 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-30510375

RESUMO

AIM: To develop a novel rat model of heterogeneous hepatic injury. METHODS: Seventy male Sprague-Dawley rats were randomly divided into a control group (n = 10) and a colchicine group (n = 60). A 0.25% colchicine solution (0.4 mL/kg) was injected via the splenic vein in the colchicine group to develop a rat model of heterogeneous hepatic injury. An equal volume of normal saline was injected via the splenic vein in the control group. At days 3, 7, and 14 and weeks 4, 8, and 12 after the operation, at least seven rats of the colchicine group were selected randomly for magnetic resonance imaging (MRI) examinations, and then they were euthanized. Ten rats of the control group underwent MRI examinations at the same time points, and then were euthanized at week 12. T2-weighted images (T2WI) and diffusion weighted imaging (DWI) were used to evaluate the heterogeneous hepatic injury. The heterogeneous injury between the left and right hepatic lobes was assessed on liver sections according to the histological scoring criteria, and correlated with the results of MRI study. RESULTS: Obvious pathological changes occurred in the hepatic parenchyma in the colchicine group. Hepatic injury scores were significantly different between the left and right lobes at each time point (P < 0.05). There was a significant difference in apparent diffusion coefficient (ADC) of DWI and liver-to-muscle ratio (LMR) of T2WI between the left and right lobes of rats in the colchicine group (P < 0.05) at each time point, and similar results were observed between the colchicine and control groups. Besides, there was a significant correlation between hepatic injury scores and ADC values or LMR (r = -0.682, P = 0.000; r = -0.245, P = 0.018). CONCLUSION: Injection with colchicine via the splenic vein can be used to successfully develop a rat model of heterogeneous hepatic injury. DWI and T2WI may help evaluate the heterogeneous injury among liver lobes.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , Colchicina/toxicidade , Modelos Animais de Doenças , Fígado/patologia , Ratos , Animais , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico por imagem , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Imagem de Difusão por Ressonância Magnética , Humanos , Fígado/irrigação sanguínea , Fígado/diagnóstico por imagem , Fígado/efeitos dos fármacos , Sistema Linfático , Masculino , Ratos Sprague-Dawley , Veia Esplênica
3.
Biol Pharm Bull ; 41(7): 1001-1005, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29962396

RESUMO

Colchicine or vincristine depolymerize microtubules, an action which blocks neuron axonal transport. Thus, these chemicals showed selective neurotoxicity in hippocampal neurons. However, the mechanism of neurotoxicity by these antimicrotubule agents has remained unclear. Our previous studies have suggested that colchicine-induced hippocampal neuron death is caused by incremental increases in intraneuronal free zinc. We have demonstrated that zinc transporter 3 gene deletion (ZnT3-/-) reduces dentate granule cell death after colchicine injection. This ZnT3-/--mediated reduction of dentate granule cell death was accompanied by a decrease in the incidence of oxidative injury. Unexpectedly, we found that ZnT3-/- mice contain a higher glutathione (GSH) level in the hippocampal neurons than wild type mice. Thus, ZnT3-/- mice showed less neuronal GSH depletion by colchicine injection, and thus less neuronal death. These results suggest that the higher levels of neuronal GSH in ZnT3-/- mice result in less dentate granule cell death after colchicine injection. In addition to colchicine, our lab also demonstrated that a chemotherapeutic agent, pacritaxel (Taxol), which is a microtubule stabilizing agent, depleted vesicular zinc in the presynaptic terminals and induced a reduction of neurogenesis. Therefore, in the present review, we discussed how antimicrotubule agent-induced neurotoxicity and cognitive impairment is associated with zinc dyshomeostasis in the brain.


Assuntos
Morte Celular/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Microtúbulos/efeitos dos fármacos , Síndromes Neurotóxicas/patologia , Moduladores de Tubulina/toxicidade , Animais , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/genética , Disfunção Cognitiva/patologia , Colchicina/toxicidade , Modelos Animais de Doenças , Hipocampo/citologia , Hipocampo/patologia , Humanos , Camundongos , Neurogênese/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/genética , Paclitaxel/farmacologia , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/patologia , Vincristina/toxicidade
4.
J Neuroimmunol ; 317: 15-23, 2018 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-29501081

RESUMO

The present study was designed to investigate the effectiveness of etoricoxib induced inhibition of neuroinflammation by studying the peripheral inflammatory markers and select immune parameters in intracerebroventricular colchicine injected rats (ICIR). Results showed time dependent upregulation of the inflammatory markers in the serum along with alterations of peripheral immune parameters in ICIR and dose-dependent recovery was observed upon administration of etoricoxib to ICIR; most of these effects were greater with the longer duration of study. The present study indicates that colchicine induced neuroinflammation may cause systemic inflammation and alteration of immune responses which are mediated by increased cox- 2 activity.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Ciclo-Oxigenase 2/imunologia , Etoricoxib/farmacologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Animais , Colchicina/administração & dosagem , Colchicina/toxicidade , Injeções Intraventriculares , Masculino , Ratos , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/toxicidade
5.
Reprod Toxicol ; 76: 103-108, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29378258

RESUMO

OBJECTIVE: The 2014 report by European Medicines Agency (EMA) restricted the use of thiocolchicoside for all reproductive-age women. In this study, we aim to expand the systematically-collected human data and discuss it within the frame provided by this report. METHODS: We identified and evaluated the outcomes of 48 prospectively recorded pregnancies referred to Terafar (Teratology Information Service, Izmir, Turkey). RESULTS: Of 42 pregnancies with first-trimester exposure and known outcomes, 31 resulted in live births, four in miscarriage and seven ended with elective terminations. There were 26 normal outcomes, two major and three minor congenital malformations among the live births. CONCLUSIONS: Despite a number of limitations, our results and previous case series collectively strengthen the view that thiocolchicoside is unlikely to be a major teratogen. EMA's 2014 report should be revised to reflect this finding, while current restrictions on use should continue until more detailed safety information is available.


Assuntos
Colchicina/análogos & derivados , Exposição Materna/efeitos adversos , Fármacos Neuromusculares/toxicidade , Resultado da Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Teratogênios/toxicidade , Colchicina/toxicidade , Feminino , Humanos , Gravidez , Resultado da Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Estudos Prospectivos
6.
Int J Mol Sci ; 18(10)2017 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-29048371

RESUMO

Our previous study demonstrated that colchicine-induced dentate granule cell death is caused by blocking axonal flow and the accumulation of intracellular zinc. Zinc is concentrated in the synaptic vesicles via zinc transporter 3 (ZnT3), which facilitates zinc transport from the cytosol into the synaptic vesicles. The aim of the present study was to identify the role of ZnT3 gene deletion on colchicine-induced dentate granule cell death. The present study used young (3-5 months) mice of the wild-type (WT) or the ZnT3-/- genotype. Colchicine (10 µg/kg) was injected into the hippocampus, and then brain sections were evaluated 12 or 24 h later. Cell death was evaluated by Fluoro-Jade B; oxidative stress was analyzed by 4-hydroxy-2-nonenal; and dendritic damage was detected by microtubule-associated protein 2. Zinc accumulation was detected by N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining. Here, we found that ZnT3-/- reduced the number of degenerating cells after colchicine injection. The ZnT3-/--mediated inhibition of cell death was accompanied by suppression of oxidative injury, dendritic damage and zinc accumulation. In addition, ZnT3-/- mice showed more glutathione content than WT mice and inhibited neuronal glutathione depletion by colchicine. These findings suggest that increased neuronal glutathione by ZnT3 gene deletion prevents colchicine-induced dentate granule cell death.


Assuntos
Proteínas de Transporte/genética , Giro Denteado/metabolismo , Deleção de Genes , Proteínas de Membrana/genética , Neurônios/metabolismo , Animais , Transporte Axonal , Proteínas de Transporte/metabolismo , Morte Celular , Colchicina/toxicidade , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Glutationa/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Proteínas de Membrana Transportadoras , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Zinco/metabolismo
7.
J Neuroimmunol ; 303: 51-61, 2017 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-28065581

RESUMO

Intracerebroventricular (i.c.v.) injection of colchicine induces neurodegeneration, memory impairments and changes of some systemic immune responses in rats. Though the role of cox 2 in these colchicine induced changes have been evaluated, the influence of nitric oxide synthase (NOS) remains to be studied. The present study was designed to assess the role of NOS on the i.c.v. colchicine induced neurodegeneration, memory impairments and changes of some systemic immune responses by inhibiting its activity with aminoguanidine. In the present study the impairments of working and reference memories, neurodegeneration (chromatolysis and plaque formation) and changes of neuroinflammatory markers in the hippocampus (increased TNF α, IL 1ß, ROS and nitrite) along with changes of serum inflammatory markers (TNF α, IL 1ß, ROS and nitrite) and alteration of systemic immune responses (higher phagocytic activity of blood WBC and splenic PMN, higher cytotoxicity and lower leukocyte adhesion inhibition index of splenic MNC) were measured in the intracerebroventricular colchicine injected rats (ICIR). Administration of aminoguanidine (p.o. 30/50mg/kg body weight) to ICIR resulted in recovery of neuroinflammation and partial prevention of neurodegeneration which could be corroborated with the partial recovery of memory impairments in this model. The recovery of serum inflammatory markers and the systemic immune responses in ICIR was also observed after administration of aminoguanidine. Therefore, the present study shows that aminoguanidine can protect the colchicine induced neurodegeneration, memory impairments, and changes of systemic immune systemic responses in ICIR by inhibiting the iNOS.


Assuntos
Colchicina/toxicidade , Inibidores Enzimáticos/uso terapêutico , Guanidinas/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Animais , Colchicina/administração & dosagem , Inibidores Enzimáticos/farmacologia , Guanidinas/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Injeções Intraventriculares , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/imunologia , Camundongos , Doenças Neurodegenerativas/induzido quimicamente , Doenças Neurodegenerativas/imunologia , Óxido Nítrico Sintase Tipo II/imunologia , Ratos
8.
Basic Clin Pharmacol Toxicol ; 120(5): 505-508, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-27862994

RESUMO

The traditional gout medication colchicine has been reported to effectively prevent atrial fibrillation recurrence after atrial fibrillation ablation or cardiac surgery in a few clinical trials. Severe adverse events have not yet been reported. The aim of the present study was to assess possible direct electrophysiological effects in an experimental whole-heart model. Ten rabbit hearts were isolated and Langendorff-perfused. Thereafter, colchicine was administered in two concentrations (1 and 3 µM). Eight endo- and epicardial monophasic action potentials and a 12-lead ECG showed a stable QT interval and action potential duration during colchicine infusion. Furthermore, there was no significant increase in dispersion of repolarization. However, colchicine induced a dose-dependent significant decrease of effective refractory period (ERP; 1 µM: -19 ms, 3 µM: -22 ms; p < 0.05). In the present study, acute infusion of colchicine in isolated rabbit hearts resulted in a reduction of ERP in the presence of a stable myocardial repolarization. This led to a significantly elevated inducibility of ventricular fibrillation. In 4 of 10 hearts, incessant ventricular fibrillation occurred. These results suggest a pro-arrhythmic or toxic effect of colchicine and underline that further clinical studies on potential adverse effects should be conducted before the drug can be recommended for routine use after atrial fibrillation ablation.


Assuntos
Potenciais de Ação/efeitos dos fármacos , Colchicina/toxicidade , Supressores da Gota/toxicidade , Fibrilação Ventricular/induzido quimicamente , Animais , Fibrilação Atrial/prevenção & controle , Colchicina/administração & dosagem , Colchicina/farmacologia , Relação Dose-Resposta a Droga , Eletrocardiografia , Técnicas Eletrofisiológicas Cardíacas , Supressores da Gota/administração & dosagem , Supressores da Gota/farmacologia , Ventrículos do Coração/efeitos dos fármacos , Coelhos
9.
Biomed Res Int ; 2016: 9161648, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-28018917

RESUMO

Genotoxic exposure to chemical substances is common, and nursing mothers could transmit harmful substances or their metabolites to their offspring through breast milk. We explored the possibility of determining genotoxic effects in the erythrocytes of breastfeeding rat pups whose mothers received a genotoxic compound while nursing. Ten groups of female rats and five pups per dam were studied. The control group received sterile water, and the experimental groups received one of three different doses of cyclophosphamide, colchicine, or cytosine-arabinoside. Blood smears were prepared from samples taken from each dam and pup every 24 h for six days. There were increased numbers of micronucleated erythrocytes (MNEs) and micronucleated polychromatic erythrocytes (MNPCEs) in the samples from pups in the experimental groups (P < 0.02) and increased MNPCE frequencies in the samples from the dams (P < 0.05). These results demonstrate the vertical transmission of the genotoxic effect of the compounds tested. In conclusion, assessing MNEs in breastfeeding neonate rats to assess DNA damage may be a useful approach for identifying genotoxic compounds and/or cytotoxic effects. This strategy could help in screening for therapeutic approaches that are genotoxic during the lactation stage and these assessments might also be helpful for developing preventive strategies to counteract harmful effects.


Assuntos
Aleitamento Materno , Eritrócitos/efeitos dos fármacos , Relações Materno-Fetais/efeitos dos fármacos , Micronúcleos com Defeito Cromossômico/efeitos dos fármacos , Animais , Colchicina/toxicidade , Ciclofosfamida/toxicidade , Citarabina/toxicidade , Feminino , Humanos , Testes de Mutagenicidade , Ratos
10.
Anticancer Res ; 36(11): 5859-5866, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27793909

RESUMO

BACKGROUND/AIM: Colchicine (COL) is a well-known and potent microtubule targeting anticancer agent. The purpose of our study was to identify conditions that increase sensitization of COL-resistant cancer cells that overexpress P-glycoprotein (P-gp). MATERIALS AND METHODS: The anti-malarial drugs chloroquine (CHL), mefloquine (MEF) and primaquine (PRI) have been shown to increase sensitization in drug-resistant KBV20C cells via P-gp inhibition. Therefore, we tested whether co-treatment of COL with PRI, CHL or MEF increases sensitivity in COL-resistant KBV20C cells over that of cells treated with COL alone and whether these effects are attributable to P-gp activity. RESULTS: Interestingly, we found that both CHL and PRI, but not MEF, reduced cytotoxicity in KBV20C cells receiving high concentrations of COL, suggesting that the effects of CHL and PRI have specific mechanisms among the anti-malarial drugs. The effects of CHL and PRI were specific to COL-resistant cells, since we did not detect a reduction in cytotoxicity in drug-sensitive parent KB cells. These data suggest that CHL and PRI inhibit the signaling pathways of COL-treated-resistant cells without P-gp inhibition. Furthermore, we studied the molecular mechanisms underlying the effects of COL-CHL co-treatment in KBV20C cells. FACS analysis, annexin V staining and western blot analysis revealed that G2 arrest and apoptosis were lower in cells co-treated with COL and CHL than in cells treated with COL alone. We also found that pH2AX, pHistone H3 and pRb expression was highly reduced in COL-CHL co-treated cells but not in COL-VIB co-treated cells. In addition, expression of the p21 protein, which correlates with drug-resistant phenotypes, increased in cells receiving COL-CHL co-treatment over that of COL-treated cells. CONCLUSION: These results suggest that reduced G2 arrest and apoptosis resulting from COL-CHL co-treatment was attributable to DNA damage and reduced cell cycle progression. These findings provide important information regarding the prevention of COL toxicity in COL-resistant cells and indicate that CHL, PRI and MEF may contribute to sensitization in COL-resistant cells.


Assuntos
Antimaláricos/farmacologia , Colchicina/toxicidade , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Histonas/metabolismo , Humanos
11.
Talanta ; 161: 804-811, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27769486

RESUMO

With the development of large-scale biologic databases, precision medicine is becoming a frontier in biomedical research. As a main focus of precision medicine study, cancer has been widely accepted as a disease born out of inherited genetic variations or accumulating genomic damage. At the single-cell level, microfluidics or lab-on-a-chip technology for cancer study is an emerging tool for improving risk assessment, diagnostic categories and therapeutic strategies. This work presents a multi-layer microchip for single-cell gene expression profiling. Treated by three drug reagents (i.e. methyl methanesulfonate, docetaxel and colchicine) with varied concentrations and time lengths, individual human breast cancer cells (MCF-7) are then lysed on-chip, and the released mRNA templates are captured and reversely transcribed into cDNA on microbead surface. Three genes (GAPDH, CDKN1A, AURKA) are amplified and quantified simultaneously through triplex real-time polymerase chain reactions (qPCR). Readout per run is set to be eighteen, and can be further improved following same approach. The microchip is able to integrate all steps of single-cell gene expression profiling, and provide precision study of drug induced genotoxicity with reduced reagents consumption per reaction and instrumental cost.


Assuntos
Aurora Quinase A/genética , Colchicina/toxicidade , Inibidor de Quinase Dependente de Ciclina p21/genética , Gliceraldeído-3-Fosfato Desidrogenases/genética , Dispositivos Lab-On-A-Chip , Metanossulfonato de Metila/toxicidade , Taxoides/toxicidade , Colchicina/farmacologia , Docetaxel , Perfilação da Expressão Gênica , Humanos , Células MCF-7 , Metanossulfonato de Metila/farmacologia , Microfluídica , Testes de Mutagenicidade , Reação em Cadeia da Polimerase em Tempo Real , Taxoides/farmacologia
12.
J Mol Neurosci ; 60(4): 421-435, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27665568

RESUMO

The neurodegeneration in colchicine induced AD rats (cAD) is mediated by cox-2 linked neuroinflammation. The importance of ROS in the inflammatory process in cAD has not been identified, which may be deciphered by blocking oxidative stress in this model by a well-known anti-oxidant vitamin C. Therefore, the present study was designed to investigate the role of vitamin C on colchicine induced oxidative stress linked neuroinflammation mediated neurodegeneration and memory impairments along with peripheral immune responses in cAD. The impairments of working and reference memory were associated with neuroinflammation and neurodegeneration in the hippocampus of cAD. Administration of vitamin C (200 and 400 mg/kg BW) in cAD resulted in recovery of memory impairments, with prevention of neurodegeneration and neuroinflammation in the hippocampus. The neuroinflammation in the hippocampus also influenced the peripheral immune responses and inflammation in the serum of cAD and all of these parameters were also recovered at 200 and 400 mg dose of vitamin C. However, cAD treated with 600 mg dose did not recover but resulted in increase of memory impairments, neurodegeneration and neuroinflammation in hippocampus along with alteration of peripheral immune responses in comparison to cAD of the present study. Therefore, the present study showed that ROS played an important role in the colchicine induced neuroinflammation linked neurodegeneration and memory impairments along with alteration of peripheral immune responses. It also appears from the results that vitamin C at lower doses showed anti-oxidant effect and at higher dose resulted in pro-oxidant effects in cAD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Ácido Ascórbico/uso terapêutico , Memória/efeitos dos fármacos , Vitaminas/uso terapêutico , Doença de Alzheimer/etiologia , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Ácido Ascórbico/administração & dosagem , Ácido Ascórbico/farmacologia , Colchicina/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação/tratamento farmacológico , Masculino , Camundongos , Estresse Oxidativo , Ratos , Espécies Reativas de Oxigênio/metabolismo , Vitaminas/administração & dosagem , Vitaminas/farmacologia
13.
Genet Mol Res ; 15(2)2016 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-27173261

RESUMO

Six different colchicine concentrations: 0, 400, 800, 1200, 1600, and 2000 ppm, in combination with four soaking time treatments (1, 2, 3, and 4 h), were selected to assess the effects on germination, vegetative growth, and flower yield components in calendula plants. The molecular diversity among the treatments was assessed using ten SRAP marker combinations. Seed soaking in colchicine significantly enhanced both the fresh and the dry shoot and root masses, flowering date, number of flowers per plant, and flower diameter. At 1200-ppm colchicine combined with a 4-h soaking time, a superior effect on seed germination was observed, whereas 800 ppm for 4 h produced the highest number of flowers and the largest flower diameter. The earliest flowering time was found at 800 ppm combined with a short soaking time (1 h), while the 4-h soaking time with 800 ppm, is recommended for growing calendula outdoors, since it enhances flower development. At the molecular level, 752 fragments were successfully amplified using the SRAP primers, with 280 genetic loci found throughout the calendula genome. The polymorphism percentage ranged from 79 to 100% and the polymorphic information content (PIC) values ranged between 0.85 and 0.97. The high number of detected loci and PIC values suggests a great power of SRAP markers in detecting mutant molecular diversity. Our results clearly show the existence of genetic variation among colchicine treated calendula plants and the clustering of the studied mutants was concordant with the colchicine concentration used.


Assuntos
Calendula/efeitos dos fármacos , Colchicina/toxicidade , Mutação , Polimorfismo Genético , Calendula/genética , Calendula/crescimento & desenvolvimento , Flores/efeitos dos fármacos , Fenótipo , Sementes/efeitos dos fármacos
14.
Chem Res Toxicol ; 29(3): 342-51, 2016 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-26881866

RESUMO

Human toxicity screening is an important stage in the development of safe drug candidates. Hepatotoxicity is one of the major reasons for the withdrawal of drugs from the market because the liver is the major organ involved in drug metabolism, and it can generate toxic metabolites. There is a need to screen molecules for drug-induced hepatotoxicity in humans at an earlier stage. Transcriptomics is a technique widely used to screen molecules for toxicity and to unravel toxicity mechanisms. To date, the majority of such studies were performed using animals or animal cells, with concomitant difficulty in interpretation due to species differences, or in human hepatoma cell lines or cultured hepatocytes, suffering from the lack of physiological expression of enzymes and transporters and lack of nonparenchymal cells. The aim of this study was to classify known hepatotoxicants on their phenotype of toxicity in humans using gene expression profiles ex vivo in human precision-cut liver slices (PCLS). Hepatotoxicants known to induce either necrosis (n = 5) or cholestasis (n = 5) were used at concentrations inducing low (<30%) and medium (30-50%) cytotoxicity, based on ATP content. Random forest and support vector machine algorithms were used to classify hepatotoxicants using a leave-one-compound-out cross-validation method. Optimized biomarker sets were compared to derive a consensus list of markers. Classification correctly predicted the toxicity phenotype with an accuracy of 70-80%. The classification is slightly better for the low than for the medium cytotoxicity. The consensus list of markers includes endoplasmic reticulum stress genes, such as C2ORF30, DNAJB9, DNAJC12, SRP72, TMED7, and UBA5, and a sodium/bile acid cotransporter (SLC10A7). This study shows that human PCLS are a useful model to predict the phenotype of drug-induced hepatotoxicity. Additional compounds should be included to confirm the consensus list of markers, which could then be used to develop a biomarker PCR-array for hepatotoxicity screening.


Assuntos
Colestase/induzido quimicamente , Perfilação da Expressão Gênica , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Necrose/induzido quimicamente , Toxicogenética , Acetaminofen/toxicidade , Idoso , Benzofuranos/toxicidade , Ácidos e Sais Biliares/toxicidade , Cloranfenicol/toxicidade , Clorpromazina/toxicidade , Colestase/genética , Colchicina/toxicidade , Ciclosporina/toxicidade , Dietilnitrosamina/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etinilestradiol/toxicidade , Feminino , Hepatócitos/metabolismo , Humanos , Masculino , Metiltestosterona/toxicidade , Pessoa de Meia-Idade , Necrose/genética , Fenótipo , Adulto Jovem
15.
J Neuroimmunol ; 291: 115-24, 2016 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-26857505

RESUMO

The neurodegeneration in colchicine induced AD (cAD) rats is linked with neuroinflammation. The inducible cox-2 present in the brain may participate in the neuroinflammatory process related to progressive neurodegeneration in cAD rats. The aim of this study is to investigate the role of cox-2 in the neurodegeneration and cognitive impairments in cAD rats. The parameters of memory (working and reference memory), inflammatory markers [IL-1ß, TNF-α, prostaglandin E2 (PGE2), cox-2 level] and histopathology of hippocampus were measured after 21-day of i.c.v. colchicine injection in rats and compared with that of control and sham operated rats. These parameters were also measured in these 3 different groups of rats after p.o. administration of 3 different doses of etoricoxib, a cox 2 inhibitor. The impairments of working and reference memory were associated with neuroinflammation and neurodegeneration in the hippocampus and increased cox-2 and PGE2 levels in hippocampus in cAD. Administration of etoricoxib in cAD rats resulted in recovery of memory impairments, neurodegeneration and neuroinflammation in hippocampus and inhibition of cox-2 and PGE2 levels in hippocampus. It appears from the results that activation of cox-2 in cAD is related to neuroinflammation involved in neurodegeneration. Colchicine induced initial neurodegeneration may trigger cascade of events for a progressive neurodegeneration where cox-2 activation plays a critical role. Moreover, this cox-2 mediated neurodegeneration is related to impairments of memory parameters. Thus, the present study showed that the impairments of memory and neurodegeneration in the hippocampus of cAD in 21-day study are mediated by cox-2 induced neuroinflammation.


Assuntos
Doença de Alzheimer/complicações , Transtornos Cognitivos/etiologia , Ciclo-Oxigenase 2/metabolismo , Encefalite/etiologia , Doenças Neurodegenerativas/etiologia , Doença de Alzheimer/induzido quimicamente , Análise de Variância , Animais , Transtornos Cognitivos/tratamento farmacológico , Colchicina/toxicidade , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Citocinas/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Encefalite/tratamento farmacológico , Etoricoxib , Injeções Intraventriculares , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Placa Amiloide/metabolismo , Piridinas/uso terapêutico , Ratos , Sulfonas/uso terapêutico , Fatores de Tempo
16.
J Immunotoxicol ; 13(4): 474-89, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26788903

RESUMO

The neurodegeneration in intracerebroventricular (icv) colchicine injected (ICIR) rats is linked with neuroinflammation. Glutamate excitotoxicity through NMDA receptors is involved with the neuroinflammation in some animal models of Alzheimer Disease (AD), but it has not been explored in ICIR rats. The aim of this study was to investigate the role of NMDA receptors (by blocking it's activity with memantine) in colchicine-induced neuroinflammation and neurodegeneration and impacts on peripheral immune parameters in ICIR rats. Levels of inflammatory markers (IL-1ß, TNFα, ROS, nitrite) in the hippocampus and serum, histopathology of the hippocampus and select peripheral immune parameters were measured 14 and 21-days after icv colchicine injection in rats. These parameters were also measured in rats that received daily per os administration of memantine (20 mg/kg) in both study durations. Neuroinflammation in the hippocampus of ICIR rats was associated with neurodegeneration (chromatolysis, plaque formation), along with changes in inflammatory markers in the serum and alterations in peripheral immune parameters (phagocytic activity of WBC and splenic PMN, cytotoxic activity/leukocyte adhesion inhibition by splenic MNC). Administration of memantine to ICIR rats resulted in mitigation of colchicine-induced inflammation in the hippocampus, inflammatory markers in the serum and neurodegeneration and also led to recovery of the measured immune endpoints; most of these effects were greater with the longer duration of study. Phagocytic activity of WBC and splenic PMN cells appeared to correlate with levels of the measured central inflammatory markers. It appears from the results that neuroinflammation might be linked with the NMDA receptor activity in ICIR rats and that this receptor is involved in the process of progressive neuroinflammation and neurodegeneration in the hippocampus of ICIR and potentially in immunomodulation in these same hosts.


Assuntos
Doença de Alzheimer/imunologia , Memantina/administração & dosagem , Inflamação Neurogênica/imunologia , Neurotoxinas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Adesão Celular , Colchicina/toxicidade , Citotoxicidade Imunológica , Modelos Animais de Doenças , Humanos , Imunomodulação , Mediadores da Inflamação/metabolismo , Infusões Intraventriculares , Masculino , Memantina/farmacologia , Camundongos , Neurotoxinas/antagonistas & inibidores , Fagocitose , Ratos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
17.
Invest New Drugs ; 34(1): 129-37, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26686345

RESUMO

The subunit protein of microtubules is tubulin, which has been the target for some of the most successful and widely used anti-tumor drugs. Most of the drugs that target tubulin bind to the ß subunit. There are many isotypes of ß-tubulin and their distributions differ among different tissues. The ßIII isotype is over-expressed in many tumors, particularly those that are aggressive, metastatic, and drug resistant. We have previously reported the design and synthesis of a series of compounds to fit the colchicine site on ßIII but not on the other isotypes. In the current study, we tested the toxicity and the anti-tumor activity of one of these compounds, CH-35, on the human breast tumor MDA-MB-231 over-expressing ßIII in a xenogeneic mouse model. We found that CH-35 was as toxic as Taxol® in vivo. Although the ßIII-over-expressing cells developed into very fast-growing tumors, CH-35 was more effective against this tumor than was Taxol. Our results suggest that CH-35 is a promising candidate for future drug development.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Colchicina/análogos & derivados , Tubulina (Proteína)/genética , Animais , Antineoplásicos/toxicidade , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Colchicina/química , Colchicina/farmacologia , Colchicina/toxicidade , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Paclitaxel/farmacologia , Paclitaxel/toxicidade , Testes de Toxicidade
18.
Environ Mol Mutagen ; 57(2): 87-113, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26581746

RESUMO

The Organisation for Economic Co-operation and Development (OECD) has launched the Adverse Outcome Pathway (AOP) Programme to advance knowledge of pathways of toxicity and improve the use of mechanistic information in risk assessment. An AOP links a molecular initiating event (MIE) to an adverse outcome (AO) through intermediate key events (KE). Here, we present the scientific evidence in support of an AOP whereby chemicals that bind to tubulin cause microtubule depolymerization resulting in spindle disorganization followed by altered chromosome alignment and segregation and the generation of aneuploidy in female germ cells, ultimately leading to aneuploidy in the offspring. Aneuploidy, an abnormal number of chromosomes that is not an exact multiple of the haploid number, is a well-known cause of human disease and represents a major cause of infertility, pregnancy failure, and serious genetic disorders in the offspring. Among chemicals that induce aneuploidy in female germ cells, a large majority impairs microtubule dynamics and spindle function. Colchicine, a prototypical chemical that binds to tubulin and causes microtubule depolymerization, is used here to illustrate the AOP. This AOP is specific to female germ cells exposed during the periovulation period. Although the majority of the data come from rodent studies, the available evidence suggests that the MIE and KEs are conserved across species and would occur in human oocytes. The development of AOPs related to mutagenicity in germ cells is expected to aid the identification of potential hazards to germ cell genomic integrity and support regulatory efforts to protect population health.


Assuntos
Aneuploidia , Mutagênicos/metabolismo , Oócitos/efeitos dos fármacos , Tubulina (Proteína)/metabolismo , Animais , Sítios de Ligação , Segregação de Cromossomos , Colchicina/toxicidade , Feminino , Humanos , Microtúbulos/efeitos dos fármacos , Mutagênicos/toxicidade , Oócitos/metabolismo , Oócitos/fisiologia , Oogênese/efeitos dos fármacos , Oogênese/genética , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Medição de Risco/métodos , Tubulina (Proteína)/química
19.
Artigo em Inglês | MEDLINE | ID: mdl-25868127

RESUMO

The liver micronucleus test is an important method to detect in vivo genotoxicants, especially those that require metabolic activation for their genotoxicity. We have already reported that structural or numerical chromosome aberration inducers have to be given before or after partial hepatectomy, respectively, to detect their genotoxicity in the liver of rats. In the present study, we assessed a twice dosing regimen, in which the genotoxicant is dosed both before and after partial hepatectomy, using the four chromosome aberration inducers used in the previous study. Two structural chromosome aberration inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used. The genotoxicant was administered to 8-week old male F344 rats one day before and again one day after the partial hepatectomy and hepatocytes were isolated 3 days after second dosing (4 days after the partial hepatectomy). As a result, all genotoxicants (structural or numerical chromosome aberration inducers) caused a dose-dependent statistically significant increase in the incidence of micronucleated hepatocytes when given both before and after partial hepatectomy. No marked difference was observed in general toxicity, relative liver weight and cell classification between single dosing regimens and twice dosing regimen of the genotoxicants. These results confirm that the twice dosing regimen, in which the test compound is dosed both before and after partial hepatectomy, can detect in vivo induction of micronucleated hepatocytes by structural or numerical chromosome aberration inducers qualitatively similar to their appropriate regimen in which the test compound is administered either before or after partial hepatectomy.


Assuntos
Hepatectomia/métodos , Hepatócitos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Testes de Mutagenicidade/métodos , Mutagênicos/toxicidade , 1,2-Dimetilidrazina/toxicidade , Animais , Benzimidazóis/toxicidade , Carbamatos/toxicidade , Aberrações Cromossômicas/induzido quimicamente , Colchicina/toxicidade , Dietilnitrosamina/toxicidade , Relação Dose-Resposta a Droga , Hepatócitos/metabolismo , Hepatócitos/patologia , Fígado/metabolismo , Fígado/patologia , Masculino , Testes para Micronúcleos/métodos , Ratos Endogâmicos F344 , Fatores de Tempo
20.
Clin Toxicol (Phila) ; 53(5): 427-32, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25858137

RESUMO

CONTEXT: Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. OBJECTIVE: To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab(™)) to protect rats against renal and other injury 24 h after colchicine ingestion. MATERIALS AND METHODS: Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. Samples of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. RESULTS: Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level; from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. DISCUSSION: Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. CONCLUSION: These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.


Assuntos
Anti-Inflamatórios/toxicidade , Antídotos/farmacologia , Colchicina/toxicidade , Fragmentos Fab das Imunoglobulinas/farmacologia , Envenenamento/tratamento farmacológico , Proteínas da Fase Aguda/urina , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/urina , Antídotos/administração & dosagem , Antídotos/farmacocinética , Biomarcadores/sangue , Biomarcadores/urina , Moléculas de Adesão Celular/urina , Colchicina/sangue , Colchicina/imunologia , Colchicina/farmacocinética , Colchicina/urina , Creatina Quinase/sangue , Diarreia/induzido quimicamente , Diarreia/diagnóstico , Diarreia/tratamento farmacológico , Fragmentos Fab das Imunoglobulinas/administração & dosagem , Fragmentos Fab das Imunoglobulinas/sangue , Fragmentos Fab das Imunoglobulinas/urina , Injeções Intraperitoneais , Rim/efeitos dos fármacos , Rim/metabolismo , Nefropatias/induzido quimicamente , Nefropatias/diagnóstico , Nefropatias/tratamento farmacológico , Lipocalinas/urina , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Taxa de Depuração Metabólica , Envenenamento/sangue , Envenenamento/urina , Proteínas Proto-Oncogênicas/urina , Ratos , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos , Ovinos , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA