Utilize este identificador para referenciar este registo:
https://hdl.handle.net/1822/40025
Título: | A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B |
Autor(es): | Garcia, Juliana Costa, Vera Marisa Carvalho, Alexandra T. P. Silvestre, Ricardo Jorge Leal Duarte, José Alberto Dourado, Daniel F. A. R. Arbo, Marcelo D. Baltazar, Teresa Oliveira, Ricardo Jorge Dinis Baptista, Paula Bastos, Maria de Lourdes Carvalho, Félix |
Palavras-chave: | α-Amanitin RNA polymerase II Polymyxin B Liver Kidney |
Data: | 2015 |
Editora: | Springer |
Revista: | Archives of Toxicology |
Citação: | Garcia, J., Costa, V. M., Carvalho, A. T. P., Silvestre, R., Duarte, J. A., Dourado, D. F. A. R., . . . Carvalho, F. (2015). A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Archives of Toxicology, 89(12), 2305-2323. doi: 10.1007/s00204-015-1582-x |
Resumo(s): | Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. a-Amanitin, the main toxin of A. phalloides, inhibits RNA polymerase II (RNAP II), causing hepatic and kidney failure. In silico studies included docking and molecular dynamics simulation coupled to molecular mechanics with generalized Born and surface area method energy decomposition on RNAP II. They were performed with a clinical drug that shares chemical similarities to a-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of a-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by a-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal a-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to a-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-a-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with a-amanitin was able to guarantee 100 % survival. Polymyxin B protects RNAP II from inactivation leading to an effective prevention of organ damage and increasing survival in a-amanitin-treated animals. The present use of clinically relevant concentrations of an already human-use-approved drug prompts the use of polymyxin B as an antidote for A. phalloides poisoning in humans. |
Tipo: | Artigo |
URI: | https://hdl.handle.net/1822/40025 |
DOI: | 10.1007/s00204-015-1582-x |
ISSN: | 0340-5761 |
Versão da editora: | http://link.springer.com/journal/204 |
Arbitragem científica: | yes |
Acesso: | Acesso aberto |
Aparece nas coleções: | ICVS - Artigos em revistas internacionais / Papers in international journals |
Ficheiros deste registo:
Ficheiro | Descrição | Tamanho | Formato | |
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garcia j_final.pdf | 8,44 MB | Adobe PDF | Ver/Abrir |