A carregar...
Publicação
Estudos da variabilidade dos níveis de expressão de genes envolvidos na metabolização de antimaláricos em Mus musculus
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 1.18 MB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
A falência terapêutica nos tratamentos antimaláricos depende de características do parasita (como a resistência por mutações no genoma do parasita) e do hospedeiro vertebrado (como a etabolização de fármacos). Este estudo teve como principal objectivo avaliar os níveis de expressão dos genes das subfamílias Cyp1A, 2B, 2C e 3A, dos transportadores de fármacos mdr1a e mdr1b e dos reguladores de
transcrição CAR e PXR, em três estirpes de Mus musculus: Balb/c, CD1 e Rockefeller. Os animais foram submetidos a tratamentos com primaquina e artemisinina, colhendo-se amostras de sangue, fígado e intestino 24 horas após a última dosagem. Para o estudo de expressão dos genes, seleccionouse a metodologia de PCR em tempo real. Analisando os resultados, verificou-se uma expressão basal
mais elevada de todos os genes, a nível hepático, nas estirpes Rockefeller e CD1, enquanto que no fragmento intestinal, duma maneira geral, ambas as estirpes possuem expressão das sub-famílias de citocromos mais baixa e dos transportadores de fármacos e reguladores de transcrição mais elevada que a referência (Balb/c). No estudo de expressão em resposta a antimaláricos, verificou-se que a nível hepático, após tratamento com artemisinina, ocorre expressão dos genes PXR, mdr1b e sub-famílias Cyp2B, 2C e 3A na estirpe CD1, mdr1a em Balb/c e inibição de Cyp2B em Rockefeller. No fragmento
intestinal, quando submetidos ao mesmo tratamento, ocorre inibição de todos os genes estudados na estirpe Balb/c, inibição de CAR, mdr1a e Cyp2B, 2C e 3A em CD1 e inibição de PXR, mdr1a, Cyp2C e 3A e expressão de CAR e Cyp2B em Rockefeller. Quando submetidos a tratamento com primaquina ocorre expressão hepática de CAR e inibição de mdr1a na estirpe Balb/c e inibição de CAR em CD1.
No fragmento intestinal, na estirpe Balb/c ocorre inibição dos genes mdr1a e da sub-família Cyp1A, em CD1 expressão de PXR e Cyp1A e em Rockefeller inibição dos reguladores de transcrição, mdr1b e
Cyp1A e expressão de mdr1a. A variabilidade inter-estirpes no metabolismo de fármacos, pode contribuir para o sucesso ou falha terapêutica. Neste estudo confirmou-se a existência dessa
variabilidade podendo ser relevante na selecção de modelos murinos para estudos de fármacos, na malária.
Therapeutic failure in malaria treatments depends on characteristics of the parasite (mutations on his genome) and vertebrate host (drug metabolic pathways). The main scope of this study was to evaluate the gene expression levels of the sub-families Cyp1A, 2B, 2C and 3A, drug transporters mdr1a and mdr1b and transcription regulators CAR and PXR, in three strains of Mus Musculus: Balb/c, CD1 e Rockefeller. Animals were submitted to treatments with primaquine and artemisinine, and samples of blood, liver and intestine, 24 hours after the last dosage were picked. For gene expression study the methodology selected was real-time PCR. The results show that, in the hepatic tissue, Rockefeller and CD1 strains possess higher basal expression for all genes, while in the intestine, in a general way, both strains have lower levels of Cyps sub-families expression and higher levels of drug transporters and transcription regulators. In the expression study in response to antimalarials, we observed that in the hepatic tissue, and after treatment with artemisinine, expression of PXR, Mdr1B genes and Cyp2B, 2C and 3A sub-families in CD1 strain, mdr1a in Balb/c and inhibition of the Cyp2B sub-family in Rockefeller, takes place. Under the same treatment, in the intestine, inhibition of all genes in study with Balb/c mice; inhibition of mdr1a and Cyp2C and 3A sub-families in CD1 and Rockefeller was observed, while inhibition of CAR and Cyp2B was only observed in CD1; further, in Rockefeller, we also observed inhibition of PXR gene and expression of CAR and Cyp2B. When submitted to treatment with primaquine, in the liver fragments, expression of CAR and inhibition of mdr1a in Balb/c strain and inhibition of CAR in CD1s was observed. In the intestine, under the same treatment, Balb/c shows inhibition of mdr1a gene and Cyp1A sub-family. In CD1 we observed expression of PXR and Cyp1A while in Rockefeller inhibition of transcription regulators, mdr1b and Cyp1A was seen, with expression of mdr1a gene.
Therapeutic failure in malaria treatments depends on characteristics of the parasite (mutations on his genome) and vertebrate host (drug metabolic pathways). The main scope of this study was to evaluate the gene expression levels of the sub-families Cyp1A, 2B, 2C and 3A, drug transporters mdr1a and mdr1b and transcription regulators CAR and PXR, in three strains of Mus Musculus: Balb/c, CD1 e Rockefeller. Animals were submitted to treatments with primaquine and artemisinine, and samples of blood, liver and intestine, 24 hours after the last dosage were picked. For gene expression study the methodology selected was real-time PCR. The results show that, in the hepatic tissue, Rockefeller and CD1 strains possess higher basal expression for all genes, while in the intestine, in a general way, both strains have lower levels of Cyps sub-families expression and higher levels of drug transporters and transcription regulators. In the expression study in response to antimalarials, we observed that in the hepatic tissue, and after treatment with artemisinine, expression of PXR, Mdr1B genes and Cyp2B, 2C and 3A sub-families in CD1 strain, mdr1a in Balb/c and inhibition of the Cyp2B sub-family in Rockefeller, takes place. Under the same treatment, in the intestine, inhibition of all genes in study with Balb/c mice; inhibition of mdr1a and Cyp2C and 3A sub-families in CD1 and Rockefeller was observed, while inhibition of CAR and Cyp2B was only observed in CD1; further, in Rockefeller, we also observed inhibition of PXR gene and expression of CAR and Cyp2B. When submitted to treatment with primaquine, in the liver fragments, expression of CAR and inhibition of mdr1a in Balb/c strain and inhibition of CAR in CD1s was observed. In the intestine, under the same treatment, Balb/c shows inhibition of mdr1a gene and Cyp1A sub-family. In CD1 we observed expression of PXR and Cyp1A while in Rockefeller inhibition of transcription regulators, mdr1b and Cyp1A was seen, with expression of mdr1a gene.
Descrição
Palavras-chave
Biologia molecular Malária Plasmodium sp Antimaláricos Genética
Contexto Educativo
Citação
Editora
Instituto de Higiene e Medicina Tropical