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Abstract(s)
O Plexo coróide (CP) está envolvido em vários processos que monitorizam e mantêm a homeostase bioquímica e celular do sistema nervoso central. Esta estrutura participa em processos de desintoxicação através da regulação dos mecanismos de transporte, da síntese e da secreção de compostos ativos, que são nocivos para o cérebro.
O CP expressa proteínas de transporte e de metabolização de fármacos, que regulam a entrega destes ao líquido cefalorraquidiano (CSF) e que participam na sua biodisponibilidade. As enzimas metabolizadoras de fármacos, nomeadamente os citocromos P450 (CYP), foram detetadas no cérebro de diversas espécies, demonstrando uma distribuição heterogénea com níveis de expressão variáveis entre as diferentes regiões do cérebro.
Apesar dos níveis de expressão das enzimas de desintoxicação serem considerados de expressão constitutiva, estudos de microarrays em moscas e mamíferos sugeriram uma expressão circadiana de vários genes de metabolização de xenobióticos. A expressão circadiana dos genes de enzimas metabolizadoras de xenobióticos pode ter implicações na toxicologia humana, os efeitos da exposição a produtos químicos, em diferentes momentos do dia. Com base nestes dados, o objetivo do presente trabalho foi verificar se os genes CYP estariam presentes no CP e se a sua expressão seria circadiana em CP de ratos fêmea e macho.
Verificamos que o CYP1B1 apresenta uma expressão circadiana no CP de ratos fêmea. Sob condições de disrupção circadiana, escuridão ou luz constante, observou-se que a expressão de CYP1B1 aumentou nas fêmeas submetidas a luminosidade constante. Além disso, a administração de estradiol (E2) e benzo(a)pireno (BaP) mostrou um aumento da expressão de CYP1B1 nas células epiteliais de CP de rato.
Em suma, o ritmo circadiano parece influenciar a expressão de CYP no CP de rato, contribuindo para estudos posteriores com o objetivo de perceber de que forma os ritmos biológicos podem interferir com a cinética de fármacos no cérebro.
Choroid plexus (CP) is involved in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the central nervous system. This structure participates in detoxification processes by regulating transport mechanisms, synthesis and secretion of active compounds that are noxious to brain. CP specifically expresses drug-metabolizing enzymes and transport proteins, which regulate cerebrospinal fluid (CSF) drug delivery, and participate in drug biodisposition. Drug-metabolizing enzymes cytochromes P450 (CYP) have been detected in the brains of multiple species, demonstrating a heterogeneous distribution with expression levels varying among different brain regions. Besides expression levels of detoxifying enzymes are considered of constitutive expression, microarray studies in flies and mammals have suggested a daily rhythmicity of that several xenobiotic metabolizing genes. The circadian expression of xenobiotic metabolizing genes may have implications for human toxicology, such as the effects of chemical exposures at different times of day. Based on these data we questioned if CYP genes are present in the CP, as well as the circadian expression in female and male rat CP. We found that CYP1B1 shows a circadian expression in the CP of female rats. Under disrupted circadian conditions, constant light or darkness, we observed that CYP1B1 expression increased in females under constant lightness. Furthermore, the administration of estradiol (E2) and benzo(a)pyrene (BaP) shown an increase of CYP1B1 expression in rat CP epithelial cells. Circadian rhythm seems to influence CYP expression in rat CP, contributing to understand how biological rhythms might interfere with drug kinetics in brain.
Choroid plexus (CP) is involved in a variety of processes that monitor and maintain the biochemical and cellular homeostasis of the central nervous system. This structure participates in detoxification processes by regulating transport mechanisms, synthesis and secretion of active compounds that are noxious to brain. CP specifically expresses drug-metabolizing enzymes and transport proteins, which regulate cerebrospinal fluid (CSF) drug delivery, and participate in drug biodisposition. Drug-metabolizing enzymes cytochromes P450 (CYP) have been detected in the brains of multiple species, demonstrating a heterogeneous distribution with expression levels varying among different brain regions. Besides expression levels of detoxifying enzymes are considered of constitutive expression, microarray studies in flies and mammals have suggested a daily rhythmicity of that several xenobiotic metabolizing genes. The circadian expression of xenobiotic metabolizing genes may have implications for human toxicology, such as the effects of chemical exposures at different times of day. Based on these data we questioned if CYP genes are present in the CP, as well as the circadian expression in female and male rat CP. We found that CYP1B1 shows a circadian expression in the CP of female rats. Under disrupted circadian conditions, constant light or darkness, we observed that CYP1B1 expression increased in females under constant lightness. Furthermore, the administration of estradiol (E2) and benzo(a)pyrene (BaP) shown an increase of CYP1B1 expression in rat CP epithelial cells. Circadian rhythm seems to influence CYP expression in rat CP, contributing to understand how biological rhythms might interfere with drug kinetics in brain.
Description
Keywords
Citocromo P450 Metabolismo dos Xenobióticos Plexo Coróide Ritmo Circadiano