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1.
Aquat Toxicol ; 234: 105798, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33799113

RESUMO

A wide variety of active pharmaceutical ingredients are released into the environment and pose a threat to aquatic organisms. Drug products using micro- and nanoparticle technology can lower these emissions into the environment by their increased bioavailability to the human patients. However, due to this enhanced efficacy, micro- and nanoscale drug delivery systems can potentially display an even higher toxicity, and thus also pose a risk to non-target organisms. Fenofibrate is a lipid-regulating agent and exhibits species-related hazards in fish. The ecotoxic effects of a fenofibrate formulation embedded into a hydroxypropyl methylcellulose microparticle matrix, as well as those of the excipients used in the formulation process, were evaluated. To compare the effects of fenofibrate without a formulation, fenofibrate was dispersed in diluted ISO water alone or dissolved in the solvent DMF and then added to diluted ISO water. The effects of these various treatments were assessed using the fish embryo toxicity test, acridine orange staining and gene expression analysis assessed by quantitative RT polymerase chain reaction. Exposure concentrations were assessed by chemical analysis. The effect threshold concentrations of fenofibrate microparticle precipitates were higher compared to the formulation. Fenofibrate dispersed in 20%-ISO-water displayed the lowest toxicity. For the fenofibrate formulation as well as for fenofibrate added as a DMF solution, greater ecotoxic effects were observed in the zebrafish embryos. The chemical analysis of the solutions revealed that more fenofibrate was present in the samples with the fenofibrate formulation as well as fenofibrate added as a DMF solution compared to fenofibrate dispersed in diluted ISO water. This could explain the higher ecotoxicity. The toxic effects on the zebrafish embryo thus suggested that the formulation as well as the solvent increased the bioavailability of fenofibrate.


Assuntos
Fenofibrato/toxicidade , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/crescimento & desenvolvimento , Animais , Cromatografia Líquida de Alta Pressão , Composição de Medicamentos , Embrião não Mamífero/efeitos dos fármacos , Embrião não Mamífero/metabolismo , Fenofibrato/análise , Fenofibrato/química , Regulação da Expressão Gênica/efeitos dos fármacos , Espectrometria de Massas , Tamanho da Partícula , Testes de Toxicidade , Peixe-Zebra/metabolismo
2.
J Vis Exp ; (169)2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33749682

RESUMO

Organoids provide a promising platform to study disease mechanism and treatments, directly in the context of human tissue with the versatility and throughput of cell culture. Mature human retinal organoids are utilized to screen potential pharmaceutical treatments for the age-related retinal degenerative disease macular telangiectasia type 2 (MacTel). We have recently shown that MacTel can be caused by elevated levels of an atypical lipid species, deoxysphingolipids (deoxySLs). These lipids are toxic to the retina and may drive the photoreceptor loss that occurs in MacTel patients. To screen drugs for their ability to prevent deoxySL photoreceptor toxicity, we generated human retinal organoids from a non-MacTel induced pluripotent stem cell (iPSC) line and matured them to a post-mitotic age where they develop all of the neuronal lineage-derived cells of the retina, including functionally mature photoreceptors. The retinal organoids were treated with a deoxySL metabolite and apoptosis was measured within the photoreceptor layer using immunohistochemistry. Using this toxicity model, pharmacological compounds that prevent deoxySL-induced photoreceptor death were screened. Using a targeted candidate approach, we determined that fenofibrate, a drug commonly prescribed for the treatment of high cholesterol and triglycerides, can also prevent deoxySL toxicity in the cells of the retina. The toxicity screen successfully identified an FDA-approved drug that can prevent photoreceptor death. This is a directly actionable finding owing to the highly disease-relevant model tested. This platform can be easily modified to test any number of metabolic stressors and potential pharmacological interventions for future treatment discovery in retinal diseases.


Assuntos
Descoberta de Drogas , Organoides/fisiologia , Retina/fisiologia , Testes de Toxicidade , Apoptose/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Corpos Embrioides/efeitos dos fármacos , Corpos Embrioides/fisiologia , Fenofibrato/toxicidade , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Organoides/efeitos dos fármacos , Células Fotorreceptoras/efeitos dos fármacos , Células Fotorreceptoras/metabolismo , Retina/citologia , Retina/efeitos dos fármacos , Esfingosina/análogos & derivados , Esfingosina/toxicidade
3.
Genomics ; 112(6): 5029-5036, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32911025

RESUMO

BACKGROUND: Breast cancer, cervical cancer, and ovarian cancer are three of the most commonly diagnosed malignancies in women, and more cancer prevention research is urgently needed. METHODS: Summary data of a large genome-wide association study of female cancers were derived from the UK biobank. We performed a transcriptome-wide association study and a gene set enrichment analysis to identify correlations between chemical exposure and aberrant expression, repression, or mutation of genes related to cancer using the Comparative Toxicogenomics Database. RESULTS: We identified five chemicals (NSC668394, glafenine, methylnitronitrosoguanidine, fenofibrate, and methylparaben) that were associated with the incidence of both breast cancer and cervical cancer. CONCLUSION: Using a transcriptome-wide association study and gene set enrichment analysis we identified environmental chemicals that are associated with an increased risk of breast cancer, cervical cancer, and ovarian cancer.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias Ovarianas/epidemiologia , Neoplasias do Colo do Útero/epidemiologia , Exposição Ambiental , Feminino , Fenofibrato/toxicidade , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glafenina/toxicidade , Humanos , Incidência , Metilnitronitrosoguanidina/toxicidade , Parabenos/toxicidade , Fenóis/toxicidade , Quinolonas/toxicidade
4.
J Toxicol Sci ; 45(8): 449-473, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32741897

RESUMO

Although peroxisome proliferator-activated receptor α (PPARα) agonists are obviously hepatocarcinogenic in rodents, they have been widely used for dyslipidemia and proven to be safe for clinical use without respect to the species difference. It is established that PPARα acts as a part of the transcription factor complex, but its precise mechanism is still unknown. Using the data of Toxicogenomics Database, reliable genes responsive to PPARα agonists, clofibrate, fenofibrate and WY-14,643, in rat liver, were extracted from both in vivo and in vitro data, and sorted by their fold increase. It was found that there were many genes responding to fibrates exclusively in vivo. Most of the in vivo specific genes appear to be unrelated to lipid metabolism and are not upregulated in the kidney. Fifty-seven genes directly related to cell proliferation were extracted from in vivo data, but they were not induced in vitro at all. Analysis of PPAR-responsive elements could not explain the observed difference in induction. To evaluate possible interaction between neighboring genes in gene expression, the correlation of the fold changes of neighboring genes for 22 drugs with various PPARα agonistic potencies were calculated for the genes showing more than 2.5 fold induction by 3 fibrates in vivo, and their genomic location was compared with that of the human orthologue. In the present study, many candidates of genes other than lipid metabolism were selected, and these could be good starting points to elucidate the mechanism of PPARα agonist-induced rodent-specific toxicity.


Assuntos
Bases de Dados Genéticas , Fenofibrato/toxicidade , Loci Gênicos/genética , Armazenamento e Recuperação da Informação/métodos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , PPAR alfa/agonistas , Pirimidinas/toxicidade , Animais , Epistasia Genética , Expressão Gênica , Estudos de Associação Genética , Masculino , Ratos Sprague-Dawley , Especificidade da Espécie
5.
Int J Toxicol ; 38(3): 192-201, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31113311

RESUMO

Because dogs are widely used in drug development as nonrodent experimental animals, using a dog model for drug-induced adverse reactions is considered to be relevant for an evaluation and investigation of a mechanism and a biomarker of clinical drug-induced adverse reactions. Skeletal muscle injury occurs by various drugs, including statins and fibrates, during drug development. However, there is almost no report of a dog model for drug-induced skeletal muscle injury. In the present study, we induced skeletal muscle injury in dogs by oral coadministration of lovastatin (LV) and fenofibrate (FF) for 4 weeks. Increases in plasma levels of creatine phosphokinase, myoglobin, miR-1, and miR-133a and degeneration/necrosis of myofibers in skeletal muscles but not in the heart were observed in LV- and FF-coadministered dogs. Plasma levels of lovastatin lactone and lovastatin acid were higher in LV- and FF-coadministered dogs than LV-administered dogs. Taken together, FF coadministration is considered to affect LV metabolism and result in skeletal muscle injury.


Assuntos
Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , Lovastatina/toxicidade , Músculo Esquelético/efeitos dos fármacos , Animais , Creatina Quinase/sangue , Cães , Interações Medicamentosas , Feminino , Fenofibrato/sangue , Fenofibrato/farmacocinética , Hipolipemiantes/sangue , Hipolipemiantes/farmacocinética , Lovastatina/sangue , Lovastatina/farmacocinética , Masculino , MicroRNAs/sangue , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Mioglobina/sangue
6.
Lipids ; 53(10): 947-960, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30592062

RESUMO

Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator-activated receptors (PPAR). PPARα is the target for the fibrate-class of drugs. Fenofibrate has been approved for its lipid-lowering effects in patients with hypercholesterolemia and hypertriglyceridemia. We were interested in understanding the expression of the energy transporters in energy-utilizing tissues like liver, heart, muscle, and adipose tissues in rat with the hypothesis that the change in transporter expression would align with the known lipid-lowering effects of PPARα agonists like fenofibrate. We found that several fatty-acid transporter proteins had significantly altered levels following 8 days of fenofibrate dosing. The mRNA levels of the highly abundant Fatp2 and Fatp5 in rat liver increased approximately twofold and decreased fourfold, respectively. Several fatty-acid-binding proteins and acyl-CoA-binding proteins had a significant increase in mRNA abundance but not the major liver fatty-acid-binding protein, Fabp1. Of particular interest was the increased liver expression of Fabp3 also known as heart-fatty acid binding protein (H-FABP or FABP3). FABP3 has been proposed as a circulating clinical biomarker for cardiomyopathy and muscle toxicity, as well as a preclinical marker for PPARα-induced muscle toxicity. Here, we show that fenofibrate induces liver mRNA levels of Fabp3 ~5000-fold resulting in an approximately 50-fold increase in FABP3 protein levels in the whole liver. This increased liver expression complicates the interpretation and potential use of FABP3 as a specific biomarker for PPARα-induced muscle toxicities.


Assuntos
Biomarcadores Farmacológicos/análise , Biomarcadores Farmacológicos/sangue , Proteína 3 Ligante de Ácido Graxo/análise , Proteína 3 Ligante de Ácido Graxo/sangue , Fenofibrato/efeitos adversos , Hipolipemiantes/efeitos adversos , Fígado/efeitos dos fármacos , Animais , Biomarcadores Farmacológicos/metabolismo , Proteína 3 Ligante de Ácido Graxo/genética , Fenofibrato/toxicidade , Coração/efeitos dos fármacos , Hipolipemiantes/toxicidade , Fígado/metabolismo , Fígado/patologia , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , RNA Mensageiro/genética , Ratos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
7.
Water Res ; 140: 56-66, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29684702

RESUMO

The aquatic environment is continually exposed to a complex mixture of chemicals, whereby effluents of wastewater treatment plants (WWTPs) are one key source. The aim of the present study was to investigate whether environmental risk assessments (ERAs) addressing individual substances are sufficiently protective for such coincidental mixtures. Based on a literature review of chemicals reported to occur in municipal WWTP effluents and mode-of-action considerations, four different types of mixtures were composed containing human pharmaceuticals, pesticides, and chemicals regulated under REACH. The experimentally determined chronic aquatic toxicity of these mixtures towards primary producers and the invertebrate Daphnia magna could be adequately predicted by the concept of concentration addition, with up to 5-fold overestimation and less than 3-fold underestimation of mixture toxicity. Effluents of a municipal WWTP had no impact on the predictability of mixture toxicity and showed no adverse effects on the test organisms. Predictive ERAs for the individual mixture components based on here derived predicted no effect concentrations (PNECs) and median measured concentrations in WWTP effluents (MCeff) indicated no unacceptable risk for any of the individual chemicals, while MCeff/PNEC summation indicated a possible risk for multi-component mixtures. However, a refined mixture assessment based on the sum of toxic units at species level indicated no unacceptable risks, and allowed for a safety margin of more than factor 10, not taking into account any dilution of WWTP effluents by surface waters. Individual substances, namely climbazole, fenofibric acid and fluoxetine, were dominating the risks of the investigated mixtures, while added risk due to the mixture was found to be low with the risk quotient being increased by less than factor 2. Yet, uncertainty remains regarding chronic mixture toxicity in fish, which was not included in the present study. The number and identity of substances composing environmental mixtures such as WWTP effluents is typically unknown. Therefore, a mixture assessment factor is discussed as an option for a prospective ERA of mixtures of unknown composition.


Assuntos
Testes de Toxicidade Crônica/métodos , Águas Residuárias/química , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/toxicidade , Animais , Araceae/efeitos dos fármacos , Clorófitas/efeitos dos fármacos , Daphnia/efeitos dos fármacos , Ecotoxicologia/métodos , Feminino , Fenofibrato/análogos & derivados , Fenofibrato/toxicidade , Fluoxetina/toxicidade , Imidazóis/toxicidade , Masculino , Praguicidas/análise , Praguicidas/toxicidade , Preparações Farmacêuticas/análise , Medição de Risco/métodos , Eliminação de Resíduos Líquidos
8.
Environ Toxicol ; 33(2): 234-247, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29134746

RESUMO

The physiological regulation of Oestrogen receptor α (ERα) and peroxisome proliferator-activated receptor alpha (PPARα) in Hepatocellular carcinoma (HCC) remains unknown. The present study we first treat the cells with fenofibrate and further investigated the possible mechanisms of 17ß-estradiol (E2 ) and/or ERα on regulating PPARα expression. We also found higher PPARα expression in the tumor area than adjacent areas and subsequently compared PPARα expression in four different hepatic cancer cell lines. Hep3B cells were found to express more PPARα than the other cell lines. Using the PPARα agonist fenofibrate, we found that fenofibrate increased Hep3B cell proliferation efficiency by increasing cell cycle proteins, such as cyclin D1 and PCNA, and inhibiting p27 and caspase 3 expressions. Next, we performed transient transfections and immuno-precipitation studies using the pTRE2/ERα plasmid to evaluate the interaction between ERα and PPARα. ERα interacted directly with PPARα and negatively regulated its function. Moreover, in Tet-on ERα over-expressed Hep3B cells, E2 treatment inhibited PPARα, its downstream gene acyl-CoA oxidase (ACO), cyclin D1 and PCNA expression and further increased p27 and caspase 3 expressions. However, over-expressed ERα plus 17-ß-estradiol (10-8 M) reversed the fenofibrate effect and induced apoptosis, which was blocked in ICI/melatonin/fenofibrate-treated cells. This study illustrates that PPARα expression and function were negatively regulated by ERα expression in Hep3B cells.


Assuntos
Receptor alfa de Estrogênio/metabolismo , Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , PPAR alfa/metabolismo , Regulação para Cima/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Estradiol/farmacologia , Receptor alfa de Estrogênio/genética , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , PPAR alfa/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ligação Proteica , RNA Mensageiro/metabolismo
9.
Toxicol Lett ; 278: 59-65, 2017 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-28698097

RESUMO

The present study aimed to verify the feasibility of an enzymatic reactive oxygen species (eROS) assay to evaluate the phototoxic risk of compounds after their metabolization. The eROS assay was designed based on the combined use of an in vitro drug metabolism system and a ROS assay. The incubation time of compounds with human hepatic S9 fractions was optimized with the use of fenofibrate (FF), a typical phototoxicant with metabolite-related phototoxicity, and the reproducibility and robustness of the eROS assay were examined using FF. The eROS assay was applied to 12 phototoxic compounds, including 7 phototoxicants with metabolite-related phototoxicity, to clarify the assay performance. According to the eROS data on singlet oxygen generation from FF and metabolic conversion profiles of FF and fenofibric acid, the incubation time of chemicals with human hepatic S9-mix was determined to be 4min. The singlet oxygen-based evaluation system in the eROS assay was found to be acceptable as a high-throughput assay because of its favorable intra-/inter-day reproducibility (coefficient of variation: ca. 8%) and robustness (Z'-factor: 0.23). Singlet oxygen data on phototoxicants with phototoxic metabolites tended to exceed 120% of control, suggesting the feasibility of the eROS assay to evaluate metabolite-related phototoxic potentials. However, further data accumulation is still needed to improve the assay performance because the eROS assay provided false predictions for some compounds. The present eROS assay may be applicable in part for evaluating the phototoxic risk of drug candidates after their metabolization in the early stage of drug discovery.


Assuntos
Bioensaio , Dermatite Fototóxica/etiologia , Fenofibrato/toxicidade , Fígado/efeitos dos fármacos , Processos Fotoquímicos , Oxigênio Singlete/metabolismo , Testes de Toxicidade/métodos , Biomarcadores/metabolismo , Biotransformação , Dermatite Fototóxica/metabolismo , Relação Dose-Resposta a Droga , Estudos de Viabilidade , Fenofibrato/metabolismo , Fenofibrato/efeitos da radiação , Humanos , Fígado/enzimologia , Reprodutibilidade dos Testes , Medição de Risco , Fatores de Tempo
10.
Physiol Res ; 65(6): 891-899, 2016 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-27539098

RESUMO

Dyslipidemia and inflammation play an important role in the pathogenesis of cardiovascular and liver disease. Fenofibrate has a well-known efficacy to reduce cholesterol and triglycerides. Combination with statins can ameliorate hypolipidemic and anti-inflammatory effects of fibrates. In the current study, we tested the anti-inflammatory and metabolic effects of fenofibrate alone and in combination with rosuvastatin in a model of inflammation and metabolic syndrome, using spontaneously hypertensive rats expressing the human C-reactive protein transgene (SHR-CRP transgenic rats). SHR-CRP rats treated with fenofibrate alone (100 mg/kg body weight) or in combination with rosuvastatin (20 mg/kg body weight) vs. SHR-CRP untreated controls showed increased levels of proinflammatory marker IL6, increased concentrations of ALT, AST and ALP, increased oxidative stress in the liver and necrotic changes of the liver. In addition, SHR-CRP rats treated with fenofibrate, or with fenofibrate combined with rosuvastatin vs. untreated controls, exhibited increased serum triglycerides and reduced HDL cholesterol, as well as reduced hepatic triglyceride, cholesterol and glycogen concentrations. These findings suggest that in the presence of high levels of human CRP, fenofibrate can induce liver damage even in combination with rosuvastatin. Accordingly, these results caution against the possible hepatotoxic effects of fenofibrate in patients with high levels of CRP.


Assuntos
Proteína C-Reativa/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Glucose/metabolismo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Testes de Função Hepática , Masculino , Síndrome Metabólica/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Transgênicos , Rosuvastatina Cálcica/farmacologia , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo
11.
Am J Physiol Gastrointest Liver Physiol ; 307(5): G564-73, 2014 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-25035112

RESUMO

Fibrates, such as fenofibrate, are peroxisome proliferator-activated receptor-α (PPARα) agonists and have been used for several decades as hypolipidemic agents in the clinic. However, contradictory observations exist on the role of fibrates in host response to acute inflammation, with unclear mechanisms. The role of PPARα in colitis was assessed using fenofibrate and Ppara-null mice. Wild-type or Ppara-null mice were subjected to acute colitis under three distinct protocols, dextran sulfate sodium, trinitrobenzenesulfonic acid, and Salmonella Typhi. Serum and colon lipidomics were analyzed to characterize the metabolic profiles by ultra-performance liquid chromatography-coupled with electrospray ionization quadrupole time-of-flight mass spectrometry. Messenger RNAs of PPARα target genes and genes involved in inflammation were determined by qunatitative PCR analysis. Fenofibrate treatment exacerbated inflammation and tissue injury in acute colitis, and this was dependent on PPARα activation. Lipidomics analysis revealed that bioactive sphingolipids, including sphingomyelins (SM) and ceramides, were significantly increased in the colitis group compared with the control group; this was further potentiated following fenofibrate treatment. In the colon, fenofibrate did not reduce the markedly increased expression of mRNA encoding TNFα found in the acute colitis model, while it decreased hydrolysis and increased synthesis of SM, upregulated RIPK3-dependent necrosis, and elevated mitochondrial fatty acid ß-oxidation, which were possibly related to the exacerbated colitis.


Assuntos
Colite/metabolismo , Colo/efeitos dos fármacos , Fenofibrato/efeitos adversos , Hipolipemiantes/efeitos adversos , PPAR alfa/metabolismo , Animais , Ceramidas/sangue , Colo/metabolismo , Colo/patologia , Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Esfingomielinas/sangue , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Cell Cycle ; 11(14): 2660-71, 2012 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-22732497

RESUMO

Anti-neoplastic potential of calorie restriction or ligand-induced activation of peroxisome proliferator activated receptors (PPARs) has been demonstrated in multiple studies; however, mechanism(s) by which tumor cells respond to these stimuli remain to be elucidated. One of the potent agonists of PPARα, fenofibrate, is a commonly used lipid-lowering drug with low systemic toxicity. Fenofibrate-induced PPARα transcriptional activity is expected to shift energy metabolism from glycolysis to fatty acid ß-oxidation, which in the long-term, could target weak metabolic points of glycolysis-dependent glioblastoma cells. The results of this study demonstrate that 25 µM fenofibrate can effectively repress malignant growth of primary glial tumor cells and glioblastoma cell lines. This cytostatic action involves G(1) arrest accompanied by only a marginal level of apoptotic cell death. Although the cells treated with 25 µM fenofibrate remain arrested, the cells treated with 50 µM fenofibrate undergo massive apoptosis, which starts after 72 h of the treatment. This delayed apoptotic event was preceded by FoxO3A nuclear accumulation, FoxO3A phosphorylation on serine residue 413, its elevated transcriptional activity and expression of FoxO-dependent apoptotic protein, Bim. siRNA-mediated inhibition of FoxO3A attenuated fenofibrate-induced apoptosis, indicating a direct involvement of this transcription factor in the fenofibrate action against glioblastoma. These properties of fenofibrate, coupled with its low systemic toxicity, make it a good candidate in support of conventional therapies against glial tumors.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/efeitos dos fármacos , Fenofibrato/toxicidade , Fatores de Transcrição Forkhead/metabolismo , Hipolipemiantes/toxicidade , Proteínas de Membrana/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteína 11 Semelhante a Bcl-2 , Linhagem Celular Tumoral , Nucléolo Celular/metabolismo , Metabolismo Energético , Proteína Forkhead Box O3 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/genética , Pontos de Checagem da Fase G1 do Ciclo Celular/efeitos dos fármacos , Glioblastoma/metabolismo , Glioblastoma/patologia , Humanos , PPAR gama/agonistas , PPAR gama/metabolismo , Fosforilação , Interferência de RNA , RNA Interferente Pequeno/metabolismo
15.
Environ Toxicol Pharmacol ; 34(1): 34-45, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22445869

RESUMO

Qualitative and quantitative approaches were tested to assess zebrafish liver effects after sub-acute exposures of certain pharmaceuticals. Carbamazepine, fenofibric acid, propranolol, sulfamethoxazole and trimethoprim were tested individually and in mixtures, including low environmental levels. Overall, data showed sex specific reactions in liver, with the major alterations being observed in males. Males treated with propranolol, fenofibric acid and with mixtures, showed an increase of vitellogenin immunostaining, compared with the control. Males also evidenced a tendency for an increased hepatic mass, after individual and mixture exposures. The volume-weighted nuclear volume of hepatocytes was high in males after exposures to either mixture, which together with the greater cytoplasmic eosinophilia and changes in cytochrome P450 1A immunoreactivity, point to an increase in metabolic/detoxification activity. These investigations revealed distinct impacts depending on the exposure type, and strengthened the importance of studying non-steroidal compounds in mixtures, including environmental levels and both sexes.


Assuntos
Fígado/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Carbamazepina/toxicidade , Citocromo P-450 CYP1A1/metabolismo , Feminino , Fenofibrato/análogos & derivados , Fenofibrato/toxicidade , Proteínas de Peixes/metabolismo , Fígado/metabolismo , Fígado/patologia , Masculino , Portugal , Propranolol/toxicidade , Rios , Sulfametoxazol/toxicidade , Trimetoprima/toxicidade , Vitelogeninas/metabolismo , Peixe-Zebra
16.
Toxicol Pathol ; 40(3): 435-47, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22301950

RESUMO

Weak peroxisome proliferator-activated receptor (PPAR) α agonists (fibrates) are used to treat dyslipidemia. This study compared the effects of the potent and selective PPARα agonist CP-778875 on peroxisomal ß-oxidation and cardiac and/or skeletal muscle injury with those of the weak PPARα agonist fenofibrate. We hypothesized that these muscle effects are mediated through the PPARα receptor, leading to increased ß-oxidation and consequent oxidative stress. CP-778875 (5 or 500 mg/kg) and fenofibrate (600 or 2,000→1,200 mg/kg, dose lowered because of intolerance) were administered to rats for six weeks. Standard end points, serum troponin I, heart and skeletal muscle ß-oxidation of palmitoyl-CoA, and acyl co-oxidase (AOX) mRNA were assessed. Both compounds dose-dependently increased the incidence and/or severity of cardiomyocyte degeneration and necrosis, heart weight, troponin I, and skeletal muscle degeneration. Mean heart ß-oxidation (3.4- to 5.1-fold control) and AOX mRNA (2.4- to 3.2-fold control) were increased with CP-778875 500 mg/kg and both doses of fenofibrate. ß-Oxidation of skeletal muscle was not affected by either compound; however, a significant increase in AOX mRNA (1.6- to 2.1-fold control) was observed with CP-778875 500 mg/kg and both doses of fenofibrate. Taken together, these findings were consistent with PPARα agonism and support the link between increased cardiac and skeletal muscle ß-oxidation and resultant muscle injury in the rat.


Assuntos
Fenofibrato/toxicidade , Coração/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , PPAR alfa/agonistas , Animais , Análise Química do Sangue , Peso Corporal , Relação Dose-Resposta a Droga , Feminino , Fenofibrato/farmacocinética , Fígado/química , Fígado/efeitos dos fármacos , Fígado/enzimologia , Fígado/patologia , Masculino , Proteínas Musculares/metabolismo , Músculo Esquelético/química , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , Miocárdio/química , Miocárdio/metabolismo , Miocárdio/patologia , NAD/metabolismo , Peroxissomos/metabolismo , Ratos , Ratos Sprague-Dawley , Testes de Toxicidade , Troponina I/sangue , Troponina I/metabolismo
17.
Annu Rev Pharmacol Toxicol ; 52: 37-56, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-21819238

RESUMO

Xenobiotics are encountered by humans on a daily basis and include drugs, environmental pollutants, cosmetics, and even components of the diet. These chemicals undergo metabolism and detoxication to produce numerous metabolites, some of which have the potential to cause unintended effects such as toxicity. They can also block the action of enzymes or receptors used for endogenous metabolism or affect the efficacy and/or bioavailability of a coadministered drug. Therefore, it is essential to determine the full metabolic effects that these chemicals have on the body. Metabolomics, the comprehensive analysis of small molecules in a biofluid, can reveal biologically relevant perturbations that result from xenobiotic exposure. This review discusses the impact that genetic, environmental, and gut microflora variation has on the metabolome, and how these variables may interact, positively and negatively, with xenobiotic metabolism.


Assuntos
Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Xenobióticos/farmacocinética , Xenobióticos/toxicidade , Animais , Disponibilidade Biológica , Ciclofosfamida/farmacocinética , Ciclofosfamida/toxicidade , Poluentes Ambientais/toxicidade , Fenofibrato/farmacocinética , Fenofibrato/toxicidade , Variação Genética , Humanos , Ifosfamida/farmacocinética , Ifosfamida/toxicidade , Inativação Metabólica , Metaboloma/genética , Metagenoma/efeitos dos fármacos , Metagenoma/genética , Proteômica/métodos
18.
J Enzyme Inhib Med Chem ; 27(2): 311-8, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22085137

RESUMO

Novel phenoxyalkylcarboxylic acid derivatives based on the natural scaffolds, flavonoids, or resveratrol were designed, synthesized, and evaluated for hypolipidaemic activity. Among the compounds, 30b lowered the triglycerides by 48.5% (P < 0.05) and total cholesterol by 44.2% (P < 0.05), respectively, and was more effective than the reference drug fenofibric acid in a Triton WR-1339-induced hyperlipidaemic mice model orally (300 mg/kg body weight). 30b also showed 59.4% triglycerides lowering in an alloxan-induced diabetic mice model orally (150 mg/kg body weight). Receptor docking studies revealed that compound 30b could interact with the amino acid residues in the ligand-binding domain essential for the activation of the PPARα. The results indicate that resveratrol should be a better scaffold to derive a new class of hypolipidaemic agents in comparison with a flavonoid scaffold.


Assuntos
Ácidos Carboxílicos/química , Diabetes Mellitus Experimental/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/síntese química , Hipolipemiantes/farmacologia , Animais , Colesterol/metabolismo , Fenofibrato/análogos & derivados , Fenofibrato/toxicidade , Flavonoides/química , Hiperlipidemias/induzido quimicamente , Espectroscopia de Ressonância Magnética , Masculino , Camundongos , Modelos Moleculares , Estrutura Molecular , Polietilenoglicóis/toxicidade , Resveratrol , Estilbenos/química , Tensoativos/toxicidade , Triglicerídeos/metabolismo
19.
Environ Toxicol Pharmacol ; 32(2): 212-7, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21843801

RESUMO

Fish embryos are a particularly vulnerable stage of development, so they represent optimal targets for screening toxicological effects of waterborne xenobiotics. Herein, the toxicity potential of two mixtures of pharmaceuticals was evaluated using a zebrafish embryo test. One of the mixtures corresponds to an environmentally realistic scenario and both have carbamazepine, fenofibric acid, propranolol, trimethoprim and sulfamethoxazole. The results evidenced morphological alterations, such as spinal deformities and yolk-sac oedemas. Moreover, heart rates decreased after both mixture exposures, e.g., at 48hpf, highest mixture versus blank control (47.8±4.9 and 55.8±3.7 beats/30s, respectively). The tail lengths also diminished significantly from 3208±145µm in blank control to 3130±126µm in highest mixture. The toxicological effects were concentration dependent. Mortality, hatching rate and the number of spontaneous movements were not affected. However, the low levels of pharmaceuticals did interfere with the normal development of zebrafish, which indicates risks for wild organisms.


Assuntos
Embrião não Mamífero/efeitos dos fármacos , Preparações Farmacêuticas , Rios/química , Poluentes Químicos da Água/toxicidade , Peixe-Zebra/embriologia , Animais , Anti-Infecciosos/toxicidade , Anticonvulsivantes/toxicidade , Anti-Hipertensivos/toxicidade , Carbamazepina/toxicidade , Relação Dose-Resposta a Droga , Embrião não Mamífero/anormalidades , Embrião não Mamífero/fisiologia , Feminino , Fenofibrato/toxicidade , Frequência Cardíaca/efeitos dos fármacos , Hipolipemiantes/toxicidade , Masculino , Portugal , Propranolol/toxicidade , Distribuição Aleatória , Sulfametoxazol/toxicidade , Trimetoprima/toxicidade
20.
Arch Toxicol ; 85(8): 1003-11, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21127841

RESUMO

Fenofibrate (FF), a peroxisome proliferator-activated receptor-alpha agonist, has been used as one of the hypolipidemic drugs in man and induces oxidative stress and promotes hepatocarcinogenesis in the liver of rodents. This chemical belongs to a class of non-genotoxic carcinogens, but DNA damage secondary to oxidative stress resulting from reactive oxygen species (ROS) generation is suspected in rodents given this chemical. To examine whether FF has genotoxic potential, partially hepatectomized F344 male rats were treated orally with 0, 1,000 or 2,000 mg/kg of FF for 2 weeks, followed by diet containing 0.15% 2 acetyl aminofluorene (2 AAF) for enhancement the tumor-promoting effect for 10 days and a single oral dose of carbon tetrachloride (CCl4) as the first experiment (liver initiation assay). As the second experiment, the in vivo liver comet assay was performed in hepatectomized rats, and the expression of some DNA repair genes was examined. In the liver initiation assay, the number and area of glutathione S-transferase placental form (GST-P)-positive single cells and foci did not increase in the FF treated groups. In the comet assay, positive results were obtained after 3 h of the last treatment of FF, and the expression of some DNA repair genes such as Apex1, Ogg1 and Mlh1 were upregulated in rats given the high dose of FF at 3 h after the treatment but not in 24 h after the treatment. The results of the present study suggest that FF causes some DNA damage in livers of rats, but is not a strong genotoxic substance leading to a DNA mutation since such DNA damage was repaired by the increased activity of some DNA repair genes.


Assuntos
Dano ao DNA/efeitos dos fármacos , Fenofibrato/toxicidade , Hipolipemiantes/toxicidade , Fígado/efeitos dos fármacos , 2-Acetilaminofluoreno/toxicidade , Administração Oral , Animais , Tetracloreto de Carbono/toxicidade , Ensaio Cometa , Reparo do DNA/genética , Relação Dose-Resposta a Droga , Fenofibrato/administração & dosagem , Regulação da Expressão Gênica , Hepatectomia , Hipolipemiantes/administração & dosagem , Fígado/metabolismo , Fígado/patologia , Masculino , PPAR alfa/agonistas , Ratos , Ratos Endogâmicos F344
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