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[PMID]:27670094
[Au] Autor:Craft RM; Haas AE; Wiley JL; Yu Z; Clowers BH
[Ad] Endereço:Department of Psychology, Washington State University, Pullman, WA, United States. Electronic address: craft@wsu.edu.
[Ti] Título:Gonadal hormone modulation of ∆ -tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats.
[So] Source:Pharmacol Biochem Behav;152:36-43, 2017 Jan.
[Is] ISSN:1873-5177
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆ -tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC's effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males' and females' behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC's behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats.
[Mh] Termos MeSH primário: Analgésicos/farmacologia
Dronabinol/antagonistas & inibidores
Dronabinol/farmacologia
Estradiol/farmacologia
Caracteres Sexuais
Testosterona/farmacologia
[Mh] Termos MeSH secundário: Animais
Catalepsia/induzido quimicamente
Catalepsia/prevenção & controle
Dronabinol/análogos & derivados
Dronabinol/sangue
Interações Medicamentosas
Feminino
Masculino
Proadifeno/farmacologia
Ratos
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Analgesics); 3XMK78S47O (Testosterone); 4TI98Z838E (Estradiol); 7J8897W37S (Dronabinol); A510CA4CBT (Proadifen)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170601
[Lr] Data última revisão:
170601
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160928
[St] Status:MEDLINE


  2 / 1409 MEDLINE  
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[PMID]:26964495
[Au] Autor:Luo Y; Yang X; Shi Q
[Ad] Endereço:Division of Systems Biology, National Center for Toxicological Research, US FDA, 3900 NCTR Road, Jefferson, AR 72079, USA.
[Ti] Título:The cytochrome P450 inhibitor SKF-525A disrupts autophagy in primary rat hepatocytes.
[So] Source:Chem Biol Interact;255:55-62, 2016 Aug 05.
[Is] ISSN:1872-7786
[Cp] País de publicação:Ireland
[La] Idioma:eng
[Ab] Resumo:The cytochrome P450 (CYP) inhibitor SKF-525A is commonly used to study drug metabolism and toxicity, particularly hepatotoxicity. By using Western blot and immunofluorescence staining, we unexpectedly found that SKF-525A at 2-20 µM caused remarkable accumulation of microtubule-associated protein light chain 3 II (LC3-II) in primary rat hepatocytes at 1, 4 and 24 h, indicating that autophagy was disrupted. SKF-525A showed no effects on chloroquine induced LC3-II accumulation, suggesting that autophagic flux was blocked, which is further supported by the increased level of the p62 protein after SKF-525A treatment. SKF-525A did not affect proteasome activities or gene expression of LC3-II or p62. Immunofluorescence of green fluorescent protein fused lysosomal-associated membrane protein 1 (LAMP1, a specific protein marker for lysosomes) and LC3-II showed that co-localization of these two proteins was partially abolished by SKF-525A, indicating that autophagosome-lysosome fusion was blocked. The other five CYP inhibitors, metyrapone, 1-aminobenzotriazole, alpha-naphthoflavone, ticlopidine, and ketoconazole, showed no effects in parallel experiments. These findings provide novel insights into the mechanisms by which various CYP inhibitors differentially affect a same drug's toxicity in hepatocytes. The data also indicate that SKF-525A is not an ideal chemical inhibitor for probing the relation between CYP mediated metabolism and toxicity in primary hepatocytes.
[Mh] Termos MeSH primário: Autofagia/efeitos dos fármacos
Inibidores das Enzimas do Citocromo P-450/toxicidade
Hepatócitos/efeitos dos fármacos
Proadifeno/toxicidade
[Mh] Termos MeSH secundário: Animais
Autofagossomos/efeitos dos fármacos
Autofagossomos/metabolismo
Autofagossomos/patologia
Células Cultivadas
Hepatócitos/metabolismo
Hepatócitos/patologia
Lisossomos/efeitos dos fármacos
Lisossomos/metabolismo
Lisossomos/patologia
Masculino
Fusão de Membrana/efeitos dos fármacos
Proteínas Associadas aos Microtúbulos/metabolismo
Complexo de Endopeptidases do Proteassoma/metabolismo
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cytochrome P-450 Enzyme Inhibitors); 0 (LC3 protein, rat); 0 (Microtubule-Associated Proteins); A510CA4CBT (Proadifen); EC 3.4.25.1 (Proteasome Endopeptidase Complex)
[Em] Mês de entrada:1701
[Cu] Atualização por classe:170125
[Lr] Data última revisão:
170125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160312
[St] Status:MEDLINE


  3 / 1409 MEDLINE  
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[PMID]:26721606
[Au] Autor:Jendzelovský R; Jendzelovská Z; Hilovská L; Koval J; Mikes J; Fedorocko P
[Ad] Endereço:Institute of Biology and Ecology, Department of Cellular Biology, Faculty of Science, Pavol Jozef Safárik University in Kosice, Moyzesova 11, 040 01 Kosice, Slovakia. Electronic address: rastislav.jendzelovsky@upjs.sk.
[Ti] Título:Proadifen sensitizes resistant ovarian adenocarcinoma cells to cisplatin.
[So] Source:Toxicol Lett;243:56-66, 2016 Jan 22.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Proadifen (SKF-525A) is a P450 monooxygenase inhibitor with potential anti-proliferative activity and the ability to potentiate the toxicity of hypericin-mediated photodynamic therapy and mitoxantrone via alteration of ABC transport proteins. Elevated expression of some ABC transporters may also determine the efficacy of cisplatin-based chemotherapy. Thus, the purpose of this study was to investigate the ability of proadifen to sensitize A2780 and A2780cis ovarian cancer cells to cisplatin (CDDP). Herein, we show for the first time that proadifen sensitized resistant ovarian cancer cells to CDDP-induced cell death. The chemosensitizing effect of proadifen on CDDP action was also confirmed by MTT assays in multicellular spheroids. The possible mechanisms responsible for the enhanced cytotoxicity of proadifen/CDDP combined treatment may be attributed to a decrease of reduced relative glutathione levels, downregulation of multidrug resistance-associated proteins 1 and 2 (MRP1, MRP2) and attenuation of survivin expression. Taken together, our results indicate that proadifen is a promising compound for further in vivo experiments related to overcoming multidrug resistance and sensitization of resistant ovarian carcinoma to CDDP.
[Mh] Termos MeSH primário: Cisplatino/farmacologia
Proadifeno/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Linhagem Celular Tumoral
Citocromo P-450 CYP3A/genética
Citocromo P-450 CYP3A/metabolismo
Regulação para Baixo
Feminino
Seres Humanos
Proteínas Inibidoras de Apoptose/genética
Proteínas Inibidoras de Apoptose/metabolismo
Membranas Mitocondriais/metabolismo
Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética
Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo
Neoplasias Epiteliais e Glandulares/tratamento farmacológico
Neoplasias Ovarianas/tratamento farmacológico
Regulação para Cima
Proteína X Associada a bcl-2/genética
Proteína X Associada a bcl-2/metabolismo
Proteína bcl-X/genética
Proteína bcl-X/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (BAX protein, human); 0 (BCL2L1 protein, human); 0 (BIRC5 protein, human); 0 (Inhibitor of Apoptosis Proteins); 0 (Multidrug Resistance-Associated Proteins); 0 (bcl-2-Associated X Protein); 0 (bcl-X Protein); 4AF605U6JN (multidrug resistance-associated protein 2); A510CA4CBT (Proadifen); EC 1.14.13.67 (CYP3A4 protein, human); EC 1.14.14.1 (Cytochrome P-450 CYP3A); Q20Q21Q62J (Cisplatin); Y49M64GZ4Q (multidrug resistance-associated protein 1)
[Em] Mês de entrada:1605
[Cu] Atualização por classe:161126
[Lr] Data última revisão:
161126
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:160102
[St] Status:MEDLINE


  4 / 1409 MEDLINE  
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[PMID]:26573510
[Au] Autor:Garnett DJ
[Ad] Endereço:Institute of Science Technology in Medicine, Keele University, Keele, Staffordshire, ST5 5BG, UK. d.j.garnett@keele.ac.uk.
[Ti] Título:Caveolae as a target to quench autoinduction of the metastatic phenotype in lung cancer.
[So] Source:J Cancer Res Clin Oncol;142(3):611-8, 2016 Mar.
[Is] ISSN:1432-1335
[Cp] País de publicação:Germany
[La] Idioma:eng
[Ab] Resumo:PURPOSE: Mevalonate pathway inhibitors are potentially useful chemotherapeutic agents showing growth inhibition and pro-apoptotic effects in cancer cells. The effects of statins and bisphosphonates on cancer growth are attributed to a reduction in protein isoprenylation. Post-translational modification and activation of GTPase binding Ras superfamily permit the recruitment of these signal proteins to membranes where they mediate the cancer phenotype. Here, the effects of three inhibitors of the mevalonate pathway and one specific inhibitor of sterol regulatory element-binding proteins were studied in both an ER-negative, Ras-inactive breast (MDA-MB-231) and lung adenocarcinoma (CaLu-1) cells in vitro. METHODS: Treated cells were subject to genome-wide gene expression profiling. A gene subset was established so that the epithelial to mesenchymal transition (EMT) could be observed and compared with signalling protein shifts. RESULTS: Within the subset, some genes normally up-regulated during EMT were asymmetrically reduced by a Δ-24 DHCR inhibitor in the lung cells. Signalling proteins associated with caveolae were down-regulated by this oxidoreductase inhibitor, while those associated with membrane rafts were up-regulated. CONCLUSIONS: This study decouples isoprenylation effects from cholesterol events per se. The data support a hypothesis that caveolae are abolished by Δ-24 DHCR intervention and it is revealed that these microdomains are vital EMT signalling structures for lung cells but not ER- and Ras-negative breast cells. When signalling by extracellular signals is quenched by removal of the hydrophilic conduit provided by caveolae, the transcriptome responds by moving the cellular identity towards quiescence.
[Mh] Termos MeSH primário: Adenocarcinoma/tratamento farmacológico
Adenocarcinoma/secundário
Antineoplásicos/uso terapêutico
Cavéolas/efeitos dos fármacos
Inibidores Enzimáticos/uso terapêutico
Neoplasias Pulmonares/tratamento farmacológico
Neoplasias Pulmonares/patologia
Ácido Mevalônico/antagonistas & inibidores
[Mh] Termos MeSH secundário: Adenocarcinoma/metabolismo
Antineoplásicos/farmacologia
Cavéolas/fisiologia
Caveolina 1/genética
Caveolina 1/metabolismo
Linhagem Celular Tumoral
Inibidores Enzimáticos/farmacologia
Transição Epitelial-Mesenquimal/efeitos dos fármacos
Transição Epitelial-Mesenquimal/genética
Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos
Seres Humanos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
Neoplasias Pulmonares/metabolismo
Neoplasias Pulmonares/secundário
Metástase Neoplásica
Proteínas do Tecido Nervoso/antagonistas & inibidores
Oxirredutases atuantes sobre Doadores de Grupo CH-CH/antagonistas & inibidores
Fenótipo
Proadifeno/farmacologia
Proadifeno/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antineoplastic Agents); 0 (Caveolin 1); 0 (Enzyme Inhibitors); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); 0 (Nerve Tissue Proteins); A510CA4CBT (Proadifen); EC 1.3.- (Oxidoreductases Acting on CH-CH Group Donors); EC 1.3.1.- (DHCR24 protein, human); S5UOB36OCZ (Mevalonic Acid)
[Em] Mês de entrada:1606
[Cu] Atualização por classe:160224
[Lr] Data última revisão:
160224
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151118
[St] Status:MEDLINE
[do] DOI:10.1007/s00432-015-2074-3


  5 / 1409 MEDLINE  
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Bracht, Adelar
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[PMID]:26552039
[Au] Autor:Bracht L; Caparroz-Assef SM; Bracht A; Bersani-Amado CA
[Ad] Endereço:Laboratory of Liver Metabolism, Department of Biochemistry, State University of Maringá, Maringá, Brazil.
[Ti] Título:Effect of the Combination of Ezetimibe and Simvastatin on Gluconeogenesis and Oxygen Consumption in the Rat Liver.
[So] Source:Basic Clin Pharmacol Toxicol;118(6):415-20, 2016 Jun.
[Is] ISSN:1742-7843
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The aim of this work was to investigate the effects of chronic treatment with the combination of ezetimibe and simvastatin on gluconeogenesis in rat liver. Rats were treated daily for 28 days with the combination of ezetimibe and simvastatin (10/40 mg/kg) by oral gavage. To measure gluconeogenesis and the associated pathways, isolated perfused rat liver was used. In addition, subcellular fractions, such as microsomes and mitochondria, were used for complementary measures of enzymatic activities. Treatment with the combination of simvastatin and ezetimibe resulted in a decrease in gluconeogenesis from pyruvate (-62%). Basal oxygen consumption of the treated animals was higher (+22%) than that of the control rats, but the resulting oxygen consumption that occurred after pyruvate infusion was 43% lower in animals treated with the combination of simvastatin and ezetimibe. Oxygen consumption in the livers from treated animals was completely inhibited by cyanide (electron transport chain inhibitor), but not by proadifen (cytochrome P450 inhibitor). Chronic treatment with ezetimibe/simvastatin decreased the activity of the key enzymes glucose-6-phosphatase and fructose-1,6-bisphosphatase by 59% and 45%, respectively, which is probably the major reason for the decreased gluconeogenesis seen in ezetimibe-/simvastatin-treated rats. It is also possible that part of the effect of this combination on gluconeogenesis and on the oxygen consumption is related to the impairment of mitochondrial energy transduction.
[Mh] Termos MeSH primário: Ezetimiba/farmacologia
Gluconeogênese/efeitos dos fármacos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia
Fígado/efeitos dos fármacos
Consumo de Oxigênio/efeitos dos fármacos
Sinvastatina/farmacologia
[Mh] Termos MeSH secundário: Animais
Cianetos/farmacologia
Combinação de Medicamentos
Inibidores Enzimáticos/farmacologia
Frutose-Bifosfatase/metabolismo
Glucose-6-Fosfatase/metabolismo
Fígado/citologia
Masculino
Microssomos Hepáticos/efeitos dos fármacos
Microssomos Hepáticos/enzimologia
Mitocôndrias Hepáticas/efeitos dos fármacos
Mitocôndrias Hepáticas/enzimologia
Proadifeno/farmacologia
Ratos
Ratos Sprague-Dawley
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Cyanides); 0 (Drug Combinations); 0 (Enzyme Inhibitors); 0 (Hydroxymethylglutaryl-CoA Reductase Inhibitors); A510CA4CBT (Proadifen); AGG2FN16EV (Simvastatin); EC 3.1.3.11 (Fructose-Bisphosphatase); EC 3.1.3.9 (Glucose-6-Phosphatase); EOR26LQQ24 (Ezetimibe)
[Em] Mês de entrada:1702
[Cu] Atualização por classe:170217
[Lr] Data última revisão:
170217
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151110
[St] Status:MEDLINE
[do] DOI:10.1111/bcpt.12522


  6 / 1409 MEDLINE  
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[PMID]:26591064
[Au] Autor:Milenina LS; Krutetskaya ZI; Naumova AA; Butov SN; Krutetskaya NI; Antonov VG
[Ti] Título:[THE EFFECT OF EPOXYGENASE INHIBITORS ON Ca(2+)-RESPONSES INDUCED BY GLUTOXIM AND MOLIXAN IN MACROPHAGES].
[So] Source:Tsitologiia;57(7):518-25, 2015.
[Is] ISSN:0041-3771
[Cp] País de publicação:Russia (Federation)
[La] Idioma:rus
[Ab] Resumo:Using Fura-2AM microfluorimetry the possible involvement of epoxygenase pathway of arachidonic acid metabolism in the effect of glutoxim and molixan on intracellular Ca2+ concentration in rat peritoneal macrophages was investigated. It was shown for the first time that preincubation of the macrophages with epoxygenase inhibitors, proadifen and econazole, significantly decreases the intracellular Ca2+ concentration increase induced by glutoxim and molixan. The addition of the epoxygenase inhibitors during the already developed store-dependent Ca(2+)-entry induced by glutoxim or molixan partially inhibits Ca(2+)-entry. The obtained data suggest the involvement of the products and/or enzymes of epoxygenase pathway of the arachidonic acid metabolism in the glutoxim and molixan effect on the Ca2+ signaling processes in macrophages.
[Mh] Termos MeSH primário: Sinalização do Cálcio/efeitos dos fármacos
Econazol/farmacologia
Inibidores Enzimáticos/farmacologia
Macrófagos Peritoneais/metabolismo
Oligopeptídeos/farmacologia
Proadifeno/farmacologia
[Mh] Termos MeSH secundário: Animais
Macrófagos Peritoneais/citologia
Masculino
Ratos
Ratos Wistar
[Pt] Tipo de publicação:ENGLISH ABSTRACT; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Oligopeptides); 0 (glutoxim); 6Z1Y2V4A7M (Econazole); A510CA4CBT (Proadifen)
[Em] Mês de entrada:1512
[Cu] Atualização por classe:151120
[Lr] Data última revisão:
151120
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:151124
[St] Status:MEDLINE


  7 / 1409 MEDLINE  
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[PMID]:26252082
[Au] Autor:Hilovská L; Jendzelovský R; Jendzelovská Z; Koval J; Fedorocko P
[Ad] Endereço:Institute of Biology and Ecology, Department of Cellular Biology, Pavol Jozef Safárik University in Kosice, SK-040 01 Kosice, Slovak Republic.
[Ti] Título:Downregulation of BCRP and anti-apoptotic proteins by proadifen (SKF-525A) is responsible for the enhanced mitoxantrone accumulation and toxicity in mitoxantrone-resistant human promyelocytic leukemia cells.
[So] Source:Int J Oncol;47(4):1572-84, 2015 Oct.
[Is] ISSN:1791-2423
[Cp] País de publicação:Greece
[La] Idioma:eng
[Ab] Resumo:Multidrug resistance caused by the overexpression of ABC transporter proteins in cancer cells remains a major obstacle limiting chemotherapy efficacy. Drugs inhibiting these transporters have been shown to increase the anti-proliferative properties of chemotherapeutics. As we previously described, proadifen, a P450 monooxygenase inhibitor, might also be able to inhibit some ABC transporters, including breast cancer resistance protein (BCRP). Because mitoxantrone (MTX) is a strong BCRP substrate and is often used in the treatment of leukemia, we investigated the effect of 24 h proadifen pre-treatment on the cytotoxicity of MTX in leukemic cell lines that are sensitive to MTX (HL-60) and MTX-resistant ABCG2-overexpressing subclone (cBCRP). We show for the first time that proadifen is able to enhance the cytotoxic properties of MTX in cBCRP cells, particularly through the inhibition of BCRP expression and activity. This proadifen-MTX synergism was also mediated by the inhibition of various cellular proteins engaged in apoptosis, including Mc-1, Bcl-xL, survivin and activation of procaspase-3. Proadifen also decreased the expression of γH2AX, which is involved in the recruitment of reparation proteins. Moreover, the inhibition of DNA damage repair proteins Ku86 and B23 after proadifen treatment indicate a possible role of proadifen in DNA repair blockage, thus suppressing the reparation rate of MTX-induced DSBs.
[Mh] Termos MeSH primário: Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia
Resistência a Medicamentos Antineoplásicos/efeitos dos fármacos
Leucemia Promielocítica Aguda/patologia
Mitoxantrona/farmacologia
Proadifeno/farmacologia
[Mh] Termos MeSH secundário: Apoptose/efeitos dos fármacos
Proteínas Reguladoras de Apoptose/efeitos dos fármacos
Proteínas Reguladoras de Apoptose/metabolismo
Western Blotting
Ciclo Celular/efeitos dos fármacos
Linhagem Celular Tumoral
Proliferação Celular/efeitos dos fármacos
Sobrevivência Celular/efeitos dos fármacos
Regulação para Baixo
Sinergismo Farmacológico
Inibidores Enzimáticos/farmacologia
Citometria de Fluxo
Seres Humanos
Potencial da Membrana Mitocondrial/efeitos dos fármacos
Reação em Cadeia da Polimerase Via Transcriptase Reversa
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Apoptosis Regulatory Proteins); 0 (Enzyme Inhibitors); A510CA4CBT (Proadifen); BZ114NVM5P (Mitoxantrone)
[Em] Mês de entrada:1608
[Cu] Atualização por classe:151001
[Lr] Data última revisão:
151001
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150808
[St] Status:MEDLINE
[do] DOI:10.3892/ijo.2015.3116


  8 / 1409 MEDLINE  
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[PMID]:25943759
[Au] Autor:de Medeiros HC; Constantin J; Ishii-Iwamoto EL; Mingatto FE
[Ad] Endereço:Laboratório de Bioquímica Metabólica e Toxicológica, UNESP - Univ Estadual Paulista, Campus de Dracena, 17900-000 Dracena, SP, Brazil.
[Ti] Título:Effect of fipronil on energy metabolism in the perfused rat liver.
[So] Source:Toxicol Lett;236(1):34-42, 2015 Jul 02.
[Is] ISSN:1879-3169
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Fipronil is an insecticide used to control pests in animals and plants that can causes hepatotoxicity in animals and humans, and it is hepatically metabolized to fipronil sulfone by cytochrome P-450. The present study aimed to characterize the effects of fipronil (10-50µM) on energy metabolism in isolated perfused rat livers. In fed animals, there was increased glucose and lactate release from glycogen catabolism, indicating the stimulation of glycogenolysis and glycolysis. In the livers of fasted animals, fipronil inhibited glucose and urea production from exogenous l-alanine, whereas ammonia and lactate production were increased. In addition, fipronil at 50µM concentration inhibited the oxygen uptake and increased the cytosolic NADH/NAD⁺ ratio under glycolytic conditions. The metabolic alterations were found both in livers from normal or proadifen-pretreated rats revealing that fipronil and its reactive metabolites contributed for the observed activity. The effects on oxygen uptake indicated that the possible mechanism of toxicity of fipronil involves impairment on mitochondrial respiratory activity, and therefore, interference with energy metabolism. The inhibitory effects on oxygen uptake observed at the highest concentration of 50µM was abolished by pretreatment of the rats with proadifen indicating that the metabolites of fipronil, including fipronil sulfone, acted predominantly as inhibitors of respiratory chain. The hepatoxicity of both the parent compound and its reactive metabolites was corroborated by the increase in the activity of lactate dehydrogenase in the effluent perfusate in livers from normal or proadifen-pretreated rats.
[Mh] Termos MeSH primário: Doença Hepática Induzida por Substâncias e Drogas/metabolismo
Canais de Cloreto/antagonistas & inibidores
Metabolismo Energético/efeitos dos fármacos
Inseticidas/toxicidade
Fígado/efeitos dos fármacos
Moduladores de Transporte de Membrana/toxicidade
Pirazóis/toxicidade
[Mh] Termos MeSH secundário: Animais
Biotransformação/efeitos dos fármacos
Doença Hepática Induzida por Substâncias e Drogas/enzimologia
Inibidores das Enzimas do Citocromo P-450/farmacologia
Transporte de Elétrons/efeitos dos fármacos
Gluconeogênese/efeitos dos fármacos
Glicogenólise/efeitos dos fármacos
Glicólise/efeitos dos fármacos
Técnicas In Vitro
Inseticidas/metabolismo
Fígado/metabolismo
Masculino
Moduladores de Transporte de Membrana/metabolismo
Mitocôndrias Hepáticas/efeitos dos fármacos
Mitocôndrias Hepáticas/enzimologia
Consumo de Oxigênio/efeitos dos fármacos
Perfusão
Proadifeno/farmacologia
Pirazóis/metabolismo
Ratos Wistar
Ureia/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Chloride Channels); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Insecticides); 0 (Membrane Transport Modulators); 0 (Pyrazoles); 8W8T17847W (Urea); A510CA4CBT (Proadifen); QGH063955F (fipronil)
[Em] Mês de entrada:1507
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:150507
[St] Status:MEDLINE


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[PMID]:23686521
[Au] Autor:Shi Q; Greenhaw J; Salminen WF
[Ad] Endereço:Division of Systems Biology, National Center for Toxicological Research, U.S. FDA, 3900 NCTR Road, Jefferson, AR, 72079, USA.
[Ti] Título:Inhibition of cytochrome P450s enhances (+)-usnic acid cytotoxicity in primary cultured rat hepatocytes.
[So] Source:J Appl Toxicol;34(8):835-40, 2014 Aug.
[Is] ISSN:1099-1263
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:(+)-Usnic acid (UA) is consumed as a dietary supplement to promote weight loss; however, dietary supplements containing UA have been associated with clinical cases of severe liver injury. UA has been shown to be hepatotoxic in rats and is extensively metabolized by hepatic cytochrome P450s (CYPs); therefore, we examined if UA metabolism results in the formation of cytotoxic metabolites or if metabolism is a detoxification process in primary rat hepatocytes. When CYP activity was suppressed by the non-isoenzyme-selective inhibitor SKF-525A (20 µM), or the CYP1A inhibitor alpha-naphthoflavone (10 µM), or the CYP3A inhibitor ketoconazole (25 µM), the cytotoxicity of UA at 3~6 µM after 3~20 h of exposure was significantly increased as measured by lactate dehydrogenase (LDH) leakage. At 2 h after UA exposure, an earlier time point prior to LDH release, these CYP inhibitors potentiated UA-induced inhibition of cellular respiration as determined by the Clark type oxygen electrode. Cellular adenosine triphosphate (ATP) depletion by UA was also exacerbated by these CYP inhibitors. The CYP2B/2C inhibitor, ticlopidine at 20 µM, showed no effects in parallel experiments. These data demonstrate that UA is bio-transformed to less toxic metabolites in rat primary hepatocytes, probably mainly by CYP1A and 3A, but not 2B/2C. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.
[Mh] Termos MeSH primário: Benzofuranos/efeitos adversos
Inibidores das Enzimas do Citocromo P-450/química
Sistema Enzimático do Citocromo P-450/metabolismo
Hepatócitos/efeitos dos fármacos
[Mh] Termos MeSH secundário: Animais
Benzoflavonas/química
Células Cultivadas
Doença Hepática Induzida por Substâncias e Drogas/etiologia
Doença Hepática Induzida por Substâncias e Drogas/patologia
Suplementos Nutricionais
Inibidores Enzimáticos/química
Cetoconazol/química
Fígado/efeitos dos fármacos
Fígado/patologia
Masculino
Mitocôndrias/efeitos dos fármacos
Mitocôndrias/metabolismo
Proadifeno/química
Ratos
Ratos Sprague-Dawley
Ticlopidina/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Benzoflavones); 0 (Benzofurans); 0 (Cytochrome P-450 Enzyme Inhibitors); 0 (Enzyme Inhibitors); 0W584PFJ77 (usnic acid); 604-59-1 (alpha-naphthoflavone); 9035-51-2 (Cytochrome P-450 Enzyme System); A510CA4CBT (Proadifen); OM90ZUW7M1 (Ticlopidine); R9400W927I (Ketoconazole)
[Em] Mês de entrada:1502
[Cu] Atualização por classe:161125
[Lr] Data última revisão:
161125
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130521
[St] Status:MEDLINE
[do] DOI:10.1002/jat.2892


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[PMID]:23299527
[Au] Autor:Kretschy N; Teichmann M; Kopf S; Atanasov AG; Saiko P; Vonach C; Viola K; Giessrigl B; Huttary N; Raab I; Krieger S; Jäger W; Szekeres T; Nijman SM; Mikulits W; Dirsch VM; Dolznig H; Grusch M; Krupitza G
[Ad] Endereço:Institute of Clinical Pathology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
[Ti] Título:In vitro inhibition of breast cancer spheroid-induced lymphendothelial defects resembling intravasation into the lymphatic vasculature by acetohexamide, isoxsuprine, nifedipin and proadifen.
[So] Source:Br J Cancer;108(3):570-8, 2013 Feb 19.
[Is] ISSN:1532-1827
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: As metastasis is the prime cause of death from malignancies, there is vibrant interest to discover options for the management of the different mechanistic steps of tumour spreading. Some approved pharmaceuticals exhibit activities against diseases they have not been developed for. In order to discover such activities that might attenuate lymph node metastasis, we investigated 225 drugs, which are approved by the US Food and Drug Administration. METHODS: A three-dimensional cell co-culture assay was utilised measuring tumour cell-induced disintegrations of the lymphendothelial wall through which tumour emboli can intravasate as a limiting step in lymph node metastasis of ductal breast cancer. The disintegrated areas in the lymphendothelial cell (LEC) monolayers were induced by 12(S)-HETE, which is secreted by MCF-7 tumour cell spheroids, and are called 'circular chemorepellent induced defects' (CCIDs). The putative mechanisms by which active drugs prevented the formation of entry gates were investigated by western blotting, NF-κB activity assay and by the determination of 12(S)-HETE synthesis. RESULTS: Acetohexamide, nifedipin, isoxsuprine and proadifen dose dependently inhibited the formation of CCIDs in LEC monolayers and inhibited markers of epithelial-to-mesenchymal-transition and migration. The migration of LECs is a prerequisite of CCID formation, and these drugs either repressed paxillin levels or the activities of myosin light chain 2, or myosin-binding subunit of myosin phosphatase. Isoxsuprine inhibited all three migration markers, and isoxsuprine and acetohexamide suppressed the synthesis of 12(S)-HETE, whereas proadifen and nifedipin inhibited NF-κB activation. Both the signalling pathways independently cause CCID formation. CONCLUSION: The targeting of different mechanisms was most likely the reason for synergistic effects of different drug combinations on the inhibition of CCID formation. Furthermore, the treatment with drug combinations allowed also a several-fold reduction in drug concentrations. These results encourage further screening of approved drugs and their in vivo testing.
[Mh] Termos MeSH primário: Acetoexamida/farmacologia
Neoplasias da Mama/tratamento farmacológico
Endotélio Linfático/efeitos dos fármacos
Isoxsuprina/farmacologia
Vasos Linfáticos/efeitos dos fármacos
Nifedipino/farmacologia
Proadifeno/farmacologia
[Mh] Termos MeSH secundário: Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo
Protocolos de Quimioterapia Combinada Antineoplásica
Western Blotting
Neoplasias da Mama/metabolismo
Neoplasias da Mama/patologia
Carcinoma Ductal de Mama/tratamento farmacológico
Carcinoma Ductal de Mama/metabolismo
Carcinoma Ductal de Mama/patologia
Adesão Celular/efeitos dos fármacos
Movimento Celular
Quimiotaxia/efeitos dos fármacos
Técnicas de Cocultura
Sinergismo Farmacológico
Endotélio Linfático/citologia
Endotélio Linfático/metabolismo
Inibidores Enzimáticos/farmacologia
Feminino
Seres Humanos
Hipoglicemiantes/farmacologia
Metástase Linfática
Vasos Linfáticos/irrigação sanguínea
Vasos Linfáticos/patologia
NF-kappa B/antagonistas & inibidores
NF-kappa B/genética
NF-kappa B/metabolismo
RNA Mensageiro/genética
Reação em Cadeia da Polimerase em Tempo Real
Reação em Cadeia da Polimerase Via Transcriptase Reversa
Transdução de Sinais/efeitos dos fármacos
Esferoides Celulares/metabolismo
Células Tumorais Cultivadas
Vasodilatadores/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Enzyme Inhibitors); 0 (Hypoglycemic Agents); 0 (NF-kappa B); 0 (RNA, Messenger); 0 (Vasodilator Agents); 59985-28-3 (12-Hydroxy-5,8,10,14-eicosatetraenoic Acid); A510CA4CBT (Proadifen); I9ZF7L6G2L (Nifedipine); QGC8W08I6I (Acetohexamide); R15UI3245N (Isoxsuprine)
[Em] Mês de entrada:1304
[Cu] Atualização por classe:150219
[Lr] Data última revisão:
150219
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:130110
[St] Status:MEDLINE
[do] DOI:10.1038/bjc.2012.580



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