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1.
Clinics (Sao Paulo) ; 70(2): 144-51, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25789524

RESUMO

OBJECTIVE: To analyze steroidogenesis-related gene expression in the rat ovary exposed to melatonin supplementation. METHODS: Thirty-two virgin adult female rats were randomized to two groups as follows: the control group GI received vehicle and the experimental group GII received melatonin supplementation (10 µg/night per animal) for 60 consecutive days. After the treatment, animals were anesthetized and the collected ovaries were immediately placed in liquid nitrogen for complementary deoxyribonucleic acid microarray analyses. A GeneChip(®) Kit Rat Genome 230 2.0 Affymetrix Array was used for gene analysis and the experiment was repeated three times for each group. The results were normalized with the GeneChip(®) Operating Software program and confirmed through analysis with the secondary deoxyribonucleic acid-Chip Analyzer (dChip) software. The data were confirmed by real-time reverse transcription polymerase chain reaction analysis. Genes related to ovarian function were further confirmed by immunohistochemistry. RESULTS: We found the upregulation of the type 9 adenylate cyclase and inhibin beta B genes and the downregulation of the cyclic adenosine monophosphate response element modulator and cytochrome P450 family 17a1 genes in the ovarian tissue of GII compared to those of the control group. CONCLUSION: Our data suggest that melatonin supplementation decreases gene expression of cyclic adenosine monophosphate, which changes ovarian steroidogenesis.


Assuntos
Adenilil Ciclases/genética , Expressão Gênica/efeitos dos fármacos , Subunidades beta de Inibinas/genética , Melatonina/farmacologia , Ovário/efeitos dos fármacos , Adenilil Ciclases/metabolismo , Animais , AMP Cíclico/metabolismo , Modulador de Elemento de Resposta do AMP Cíclico/genética , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Suplementos Nutricionais , Feminino , Subunidades beta de Inibinas/metabolismo , Melatonina/metabolismo , Modelos Animais , Ovário/metabolismo , RNA Complementar/isolamento & purificação , Distribuição Aleatória , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real/métodos , Esteroide 17-alfa-Hidroxilase/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Análise Serial de Tecidos/métodos , Regulação para Cima
2.
Toxicol Lett ; 192(3): 271-7, 2010 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19913079

RESUMO

Cytochrome P450c17 (CYP17) has been linked to various hormone-related diseases, including breast cancer, thus being a potential target for cancer chemoprevention. We studied the naturally occurring phytochemical enterolactone (ENL) and 13 VIOXX-related lactone derivatives (CRI-1 to CRI-13) for their effects on CYP17 activity and expression and on cell cycle status in the human H295R adrenocorticocarcinoma cell line. Of the tested compounds, only CRI-3, -7, -10 and -12 showed to be inhibitors of CYP17 activity in H295R cells. This inhibition was not due to decreased mRNA expression, but was apparently caused by post-translational modification of the CYP17 enzyme. The MAPK kinase (MEK) inhibitor PD98059 induced CYP17 activity by 24%, while co-incubation of the CRI-s with PD98059, reduced CYP17 activity even further than the reduction caused by the CRI-s alone. In addition, CRI-3, -7, -10 and -12 arrested the cell cycle in the G(2)/M phase. The structure-activity similarities of the CRI-s with known micro-tubule binding agents strongly suggest that cell cycle arrest is a result of interaction with tubulin. We conclude that the proposed cancer chemopreventive actions of ENL are not mediated through interaction with CYP17 or cell cycle status. Of the VIOXX-related lactone derivatives, CRI-7 could prove useful in the prevention of hormone-dependent cancers, such as breast cancer, since in vitro it shows low cytotoxicity, it is a potent inhibitor of CYP17 activity and strong inducer of cell cycle arrest.


Assuntos
4-Butirolactona/análogos & derivados , Neoplasias do Córtex Suprarrenal/enzimologia , Carcinoma Adrenocortical/enzimologia , Lactonas/farmacologia , Lignanas/farmacologia , Fitoestrógenos/farmacologia , Esteroide 17-alfa-Hidroxilase/efeitos dos fármacos , Sulfonas/farmacologia , 4-Butirolactona/farmacologia , Neoplasias do Córtex Suprarrenal/fisiopatologia , Carcinoma Adrenocortical/fisiopatologia , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Indução Enzimática/efeitos dos fármacos , Flavonoides/farmacologia , Expressão Gênica/efeitos dos fármacos , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Neoplasias Hormônio-Dependentes/prevenção & controle , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/antagonistas & inibidores , Esteroide 17-alfa-Hidroxilase/biossíntese , Relação Estrutura-Atividade
3.
BMC Genomics ; 9: 487, 2008 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-18925944

RESUMO

BACKGROUND: Dichlorodiphenyltrichloroethane (DDT) is a persistent estrogenic organochlorine pesticide that is a rodent hepatic tumor promoter, with inconclusive carcinogenicity in humans. We have previously reported that o, p'-DDT elicits primarily PXR/CAR-mediated activity, rather than ER-mediated hepatic responses, and suggested that CAR-mediated effects, as opposed to ER-mediated effects, may be more important in tumor promotion in the rat liver. To further characterize species-specific hepatic responses, gene expression analysis, with complementary histopathology and tissue level analyses were investigated in immature, ovariectomized C57BL/6 mice treated with 300 mg/kg o, p'-DDT, and compared to Sprague-Dawley rat data. RESULTS: Rats and mice exhibited negligible histopathology with rapid o, p'-DDT metabolism. Gene expression profiles were also similar, exhibiting PXR/CAR regulation with the characteristic induction of Cyp2b10 and Cyp3a11. However, PXR-specific target genes such as Apoa4 or Insig2 exhibited more pronounced induction compared to CAR-specific genes in the mouse. In addition, mouse Car mRNA levels decreased, possibly contributing to the preferential activation of mouse PXR. ER-regulated genes Cyp17a1 and Cyp7b1 were also induced, suggesting o, p'-DDT also elicits ER-mediated gene expression in the mouse, while ER-mediated effects were negligible in the rat, possibly due to the inhibitory effects of CAR on ER activities. In addition, o, p'-DDT induced Gadd45a, Gadd45b and Cdkn1, suggesting DNA damage may be an additional risk factor. Furthermore, elevated blood DHEA-S levels at 12 h after treatment in the mouse may also contribute to the endocrine-related effects of o, p'-DDT. CONCLUSION: Although DDT is known to cause rodent hepatic tumors, the marked species differences in PXR/CAR structure, expression patterns and ligand preference as well as significant species-specific differences in steroidogenesis, especially CYP17A1 expression and activity, confound the extrapolation of these results to humans. Nevertheless, the identification of potential modes of action as well as species-specific responses may assist in the selection and further development of more appropriate models for assessing the toxicity of DDT to humans and wildlife.


Assuntos
Diclorodifenil Dicloroetileno/toxicidade , Inseticidas/toxicidade , Fígado/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Esteroides/metabolismo , Fatores de Transcrição/metabolismo , Androstenodiona/sangue , Animais , Análise por Conglomerados , Receptor Constitutivo de Androstano , Sulfato de Desidroepiandrosterona/sangue , Diclorodifenil Dicloroetileno/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Inseticidas/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise de Sequência com Séries de Oligonucleotídeos , Receptor de Pregnano X , Ratos , Ratos Sprague-Dawley , Receptores Citoplasmáticos e Nucleares/efeitos dos fármacos , Receptores Citoplasmáticos e Nucleares/genética , Receptores de Estrogênio/efeitos dos fármacos , Receptores de Estrogênio/genética , Receptores de Esteroides/efeitos dos fármacos , Receptores de Esteroides/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie , Esteroide 17-alfa-Hidroxilase/efeitos dos fármacos , Esteroide 17-alfa-Hidroxilase/genética , Esteroide 17-alfa-Hidroxilase/metabolismo , Fatores de Transcrição/efeitos dos fármacos , Fatores de Transcrição/genética
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