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1.
Food Chem Toxicol ; 46(4): 1239-48, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17976884

RESUMO

Coffee consumption has been associated with a significant decrease in the risk of developing chronic diseases such as Parkinson disease, diabetes type-2 and several types of cancers (e.g. colon, liver). In the present study, a coffee-dependent induction of enzymes involved in xenobiotic detoxification processes was observed in rat liver and primary hepatocytes. In addition, coffee was found to induce the mRNA and protein expression of enzymes involved in cellular antioxidant defenses. These inductions were correlated with the activation of the Nrf2 transcription factor as shown using an ARE-reporter luciferase assay. The induction of detoxifying enzymes GSTs and AKR is compatible with a protection against both genotoxicity and cytotoxicity of aflatoxin B1 (AFB1). This hypothesis was confirmed in in vitro and ex vivo test systems, where coffee reduced both AFB1-DNA and protein adducts. Interestingly, coffee was also found to inhibit cytochrome CYP1A1/2, indicating that other mechanisms different from a stimulation of detoxification may also play a significant role in the chemoprotective effects of coffee. Further investigations in either human liver cell line and primary hepatocytes indicated that the chemoprotective effects of coffee against AFB1 genotoxicity are likely to be of relevance for humans. These data strongly suggest that coffee may protect against the adverse effects of AFB1. In addition, the coffee-mediated stimulation of the Nrf2-ARE pathway resulting in increased endogenous defense mechanisms against electrophilic but also oxidative insults further support that coffee may be associated with a protection against various types of chemical stresses.


Assuntos
Anticarcinógenos/farmacologia , Café/química , Neoplasias Hepáticas Experimentais/prevenção & controle , Fator 2 Relacionado a NF-E2/biossíntese , Aflatoxina B1/toxicidade , Animais , Antioxidantes/metabolismo , Western Blotting , Carcinógenos/toxicidade , Citocromo P-450 CYP1A1/metabolismo , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A , Sistema Enzimático do Citocromo P-450/metabolismo , Relação Dose-Resposta a Droga , Genes Reporter , Glutationa/metabolismo , Glutationa Transferase/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/enzimologia , Hepatócitos/patologia , Humanos , Neoplasias Hepáticas Experimentais/induzido quimicamente , Neoplasias Hepáticas Experimentais/enzimologia , Luciferases/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Elementos Reguladores de Transcrição , Reação em Cadeia da Polimerase Via Transcriptase Reversa
2.
Toxicol Sci ; 89(1): 120-34, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16251485

RESUMO

Ochratoxin A (OTA) is a mycotoxin occurring naturally in a wide range of food commodities. In animals, it has been shown to cause a variety of adverse effects, nephrocarcinogenicity being the most prominent. Because of its high toxic potency and the continuous exposure of the human population, OTA has raised public health concerns. There is significant debate on how to use the rat carcinogenicity data to assess the potential risk to humans. In this context, the question of the mechanism of action of OTA appears of key importance and was studied through the application of a toxicogenomics approach. Male Fischer rats were fed OTA for up to 2 years. Renal tumors were discovered during the last 6 months of the study. The total tumor incidence reached 25% at the end of the study. Gene expression profile was analyzed in groups of animals taken in intervals from 7 days to 12 months. Tissue-specific responses were observed in kidney versus liver. For selected genes, microarray data were confirmed at both mRNA and protein levels. In kidney, several genes known as markers of kidney injury and cell regeneration were significantly modulated by OTA. The expression of genes known to be involved in DNA synthesis and repair, or genes induced as a result of DNA damage, was only marginally modulated. Very little or no effect was found amongst genes associated with apoptosis. Alterations of gene expression indicating effects on calcium homeostasis and a disruption of pathways regulated by the transcription factors hepatocyte nuclear factor 4 alpha (HNF4alpha) and nuclear factor-erythroid 2-related factor 2 (Nrf2) were observed in the kidney but not in the liver. Previous data have suggested that a reduction in HNF4alpha may be associated with nephrocarcinogenicity. Many Nrf2-regulated genes are involved in chemical detoxication and antioxidant defense. The depletion of these genes is likely to impair the defense potential of the cells, resulting in chronic elevation of oxidative stress in the kidney. The inhibition of defense mechanism appears as a highly plausible new mechanism, which could contribute to OTA carcinogenicity.


Assuntos
Carcinógenos/toxicidade , Epigênese Genética , Perfilação da Expressão Gênica , Neoplasias Renais/induzido quimicamente , Micotoxinas/toxicidade , Ocratoxinas/toxicidade , Administração Oral , Animais , Biomarcadores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Neoplasias Renais/genética , Neoplasias Renais/patologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Ratos , Ratos Endogâmicos F344 , Toxicogenética
3.
J Comp Neurol ; 509(5): 514-25, 2008 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-18537122

RESUMO

To determine the role in chemosensation of intestinal solitary cells that express taste receptors and Trpm5, we carried out a microarray study of the transcriptome of FACS-sorted transgenic mouse intestinal cells expressing enhanced green fluorescent protein (eGFP) under the control of the Trpm5 promoter and compared it with that of intestinal cells that do not express eGFP. The findings of the study are: 1) Morphology and expression of markers show that most eGFP+ cells are brush cells. 2) The majority of proteins known to be involved in taste signal transduction are expressed in the eGFP+ cells, although the isoforms are not always the same. 3) eGFP+ cells express pre- and postsynaptic markers and nerves are often found in close proximity. 4) Several genes that play a role in inflammation are expressed specifically in eGFP+ cells. Furthermore, these cells express the entire biosynthesis pathway of leucotriene C4, an eicosanoid involved in modulation of intestinal smooth muscle contraction. 5) Angiotensinogen, renin, and succinate receptor genes are expressed in the eGFP+ cells, suggesting a role in the regulation of water and sodium transport, vasomotricity, and blood pressure. These data suggest that the Trpm5-expressing cells integrate many signals, including chemical signals from ingested food, and that they may regulate several physiological functions of the gastrointestinal tract.


Assuntos
Regulação da Expressão Gênica/fisiologia , Mediadores da Inflamação/fisiologia , Intestino Delgado/metabolismo , Intestino Delgado/patologia , Neurônios/metabolismo , Neurônios/patologia , Canais de Cátion TRPM/biossíntese , Animais , Ingestão de Alimentos/genética , Ingestão de Alimentos/fisiologia , Marcadores Genéticos/fisiologia , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Humanos , Mediadores da Inflamação/metabolismo , Intestino Delgado/ultraestrutura , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microvilosidades/genética , Microvilosidades/metabolismo , Microvilosidades/ultraestrutura , Neurônios/ultraestrutura , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Transdução de Sinais/genética , Canais de Cátion TRPM/genética
4.
Toxicol Appl Pharmacol ; 224(2): 174-81, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17651772

RESUMO

Kidney samples of male Fischer 344 (F-344) rats fed a carcinogenic dose of OTA over 7 days, 21 days and 12 months were analysed for various cell signalling proteins known to be potentially involved in chemical carcinogenicity. OTA was found to increase the phosphorylation of atypical-PKC. This was correlated with a selective downstream activation of the MAP-kinase extracellular regulated kinases isoforms 1 and 2 (ERK1/2) and of their substrates ELK1/2 and p90RSK. Moreover, analysis of effectors acting upstream of PKC indicated a possible mobilisation of the insulin-like growth factor-1 receptor (lGFr) and phosphoinositide-dependent kinase-1 (PDK1) system. An increased histone deacetylase (HDAC) enzymatic activity associated with enhanced HDAC3 protein expression was also observed. These findings are potentially relevant with respect to the understanding of OTA nephrocarcinogenicity. HDAC-induced gene silencing has previously been shown to play a role in tumour development. Furthermore, PKC and the MEK-ERK MAP-kinase pathways are known to play important roles in cell proliferation, cell survival, anti-apoptotic activity and renal cancer development.


Assuntos
Carcinógenos/toxicidade , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Ocratoxinas/toxicidade , Proteínas Quinases Dependentes de 3-Fosfoinositídeo , Animais , Western Blotting , Carcinógenos/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/metabolismo , Rim/metabolismo , Neoplasias Renais/induzido quimicamente , Neoplasias Renais/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Ocratoxinas/administração & dosagem , Fosforilação , Proteínas Serina-Treonina Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Ratos , Ratos Endogâmicos F344 , Receptor IGF Tipo 1/efeitos dos fármacos , Receptor IGF Tipo 1/metabolismo , Proteínas Quinases S6 Ribossômicas 90-kDa/efeitos dos fármacos , Proteínas Quinases S6 Ribossômicas 90-kDa/metabolismo , Fatores de Tempo , Proteínas Elk-1 do Domínio ets/efeitos dos fármacos , Proteínas Elk-1 do Domínio ets/metabolismo
5.
Biochem Biophys Res Commun ; 306(2): 488-95, 2003 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-12804590

RESUMO

The coffee-specific diterpenes cafestol and kahweol (C+K) have been identified as two important chemoprotective agents in coffee. In the present study, the potential preventive effects of C+K against the genotoxicity of B[a]P were investigated in rat primary hepatocytes and in human bronchial Beas-2B cells. Several independent mechanisms were identified and their respective contribution to the overall protective effects was determined. A marked dose-dependent inhibition by C+K of B[a]P DNA-binding was found in cells of both origins. However, data showed that the significant induction by C+K of the detoxifying enzyme GST-Yp subunit is the key mechanism of protection against B[a]P DNA-binding in rat liver. In contrast, the phase I-mediated mechanism where C+K produce an inhibition of CYP 1A1 induction by B[a]P is of key significance for the C+K protection in human Beas-2B cells. Moreover, this effect suggests a novel mechanism of chemoprotection by the coffee diterpenes cafestol and kahweol.


Assuntos
Diterpenos/farmacologia , Animais , Benzo(a)pireno , Western Blotting , Sobrevivência Celular , Células Cultivadas , Café , Citocromo P-450 CYP1A1/antagonistas & inibidores , Citocromo P-450 CYP1A1/metabolismo , DNA/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Ácido Etacrínico/farmacologia , Glutationa Transferase/metabolismo , Humanos , Ratos , Ratos Sprague-Dawley , Fatores de Tempo , Células Tumorais Cultivadas
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