A carregar...
Publicação
O Cobre nas doenças de Wilson e Menkes
| Nome: | Descrição: | Tamanho: | Formato: | |
|---|---|---|---|---|
| 826.22 KB | Adobe PDF |
Autores
Orientador(es)
Resumo(s)
O cobre é um elemento de transição essencial para o organismo humano. É importante, nomeadamente, para o desenvolvimento neurológico já que existem enzimas envolvidas neste processo cuja atividade depende do cobre. Assim, disfunções genéticas do metabolismo deste elemento provocam níveis séricos de cobre anormais, resultando em graves consequências para o indivíduo.
A proteína ATP7A é responsável pela absorção intestinal do cobre ingerido na dieta, que depois é transportado até ao fígado. Aí, o cobre pode, por exemplo, ser armazenado numa forma não tóxica ou ser excretado. O processo de excreção biliar do cobre é regulado pela proteína ATP7B. Assim, mutações nos genes que codificam as proteínas ATP7A e ATP7B causam disfunções na homeostasia do cobre.
A sub-expressão de ATP7B provoca reduzidos níveis séricos de cobre e ceruloplasmina e uma acumulação de cobre intracelular na forma livre, o que provoca lesões celulares em vários tecidos – principalmente no fígado e no cérebro (doença de Wilson).
Já mutações no gene ATP7A diminuem a atividade das enzimas dependentes do cobre uma vez que este elemento não é absorvido, verificando-se reduzidos níveis séricos de cobre e ceruloplasmina e, consequentemente, um atraso no desenvolvimento cerebral do indivíduo (doença de Menkes).
A terapêutica da doença de Wilson consiste na administração de agentes complexantes do catião cobre (D-penicilamina, trietilenotetramina e tetratiomolibdato) e/ou sais de zinco. Contudo, apresentam graves efeitos secundários e algumas manifestações podem mesmo ser agravadas, pelo que a terapêutica não é segura.
O tratamento da doença de Menkes baseia-se na administração de cobre por via subcutânea. Contudo, não é eficaz porque mesmo com níveis séricos de cobre normais, este elemento é incapaz de atravessar a barreira hematoencefálica (porque a ATP7A não é expressa), não se conseguindo evitar o atraso no desenvolvimento cerebral do doente.
Assim, é necessário procurar novos agentes terapêuticos e assegurar o diagnóstico precoce destas doenças.
Copper is an essential trace element. It is important, for instance, for neurological development because there are copper-dependent enzymes involved in this process. Therefore, genetic disorders of copper metabolism cause abnormal copper serum levels, which lead to severe consequences in neurological development. ATP7A protein is responsible for the intestinal absorption of copper from the diet, which is, later, transported to the liver. Within hepatocytes copper can, for instance, be stored in a non-toxic form or it can be excreted. Copper’s biliary excretion is regulated by ATP7B protein. Mutations in the genes that encode proteins ATP7A and ATP7B cause disturbance in copper homeostasis. Underexpression of ATP7B causes reduced copper and ceruloplasmin serum levels and leads to copper accumulation within cells in its free form, which causes cellular damage in several tissues, mainly the liver and the brain (Wilson’s disease). Mutations in the ATP7A gene cause decreased activity of copper-dependent enzymes because copper is not absorbed by enterocytes. Patients exhibit reduced copper and ceruloplasmin serum levels and, consequently, there is a delayed neurological development (Menkes disease). Wilson’s disease is treated by the administration of agents that complex copper cation (D-pencillamine, triethylenetetramine and tetrathiomolybdate) and/or zinc salts. However, these complexing agents show severe side effects and some symptoms can even be aggravated – which is why the therapy is not safe. Treatment of Menkes disease consists in the subcutaneous administration of copper. However it is not effective because, even with normal copper serum levels, this element can’t cross the blood-brain barrier (because ATP7A is not expressed). Therefore, there is no way to avoid the delayed neurological development. There is a necessity to find new molecules to treat these hereditary diseases. An early diagnosis is also crucial.
Copper is an essential trace element. It is important, for instance, for neurological development because there are copper-dependent enzymes involved in this process. Therefore, genetic disorders of copper metabolism cause abnormal copper serum levels, which lead to severe consequences in neurological development. ATP7A protein is responsible for the intestinal absorption of copper from the diet, which is, later, transported to the liver. Within hepatocytes copper can, for instance, be stored in a non-toxic form or it can be excreted. Copper’s biliary excretion is regulated by ATP7B protein. Mutations in the genes that encode proteins ATP7A and ATP7B cause disturbance in copper homeostasis. Underexpression of ATP7B causes reduced copper and ceruloplasmin serum levels and leads to copper accumulation within cells in its free form, which causes cellular damage in several tissues, mainly the liver and the brain (Wilson’s disease). Mutations in the ATP7A gene cause decreased activity of copper-dependent enzymes because copper is not absorbed by enterocytes. Patients exhibit reduced copper and ceruloplasmin serum levels and, consequently, there is a delayed neurological development (Menkes disease). Wilson’s disease is treated by the administration of agents that complex copper cation (D-pencillamine, triethylenetetramine and tetrathiomolybdate) and/or zinc salts. However, these complexing agents show severe side effects and some symptoms can even be aggravated – which is why the therapy is not safe. Treatment of Menkes disease consists in the subcutaneous administration of copper. However it is not effective because, even with normal copper serum levels, this element can’t cross the blood-brain barrier (because ATP7A is not expressed). Therefore, there is no way to avoid the delayed neurological development. There is a necessity to find new molecules to treat these hereditary diseases. An early diagnosis is also crucial.
Descrição
Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2016
Palavras-chave
Cobre Ceruloplasmina Doença de Wilson Doença de Menkes Agentes quelantes Mestrado Integrado - 2016