Please use this identifier to cite or link to this item: https://hdl.handle.net/1822/40025

TitleA breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B
Author(s)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
Keywordsα-Amanitin
RNA polymerase II
Polymyxin B
Liver
Kidney
Issue date2015
PublisherSpringer
JournalArchives of Toxicology
CitationGarcia, 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
Abstract(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.
TypeArticle
URIhttps://hdl.handle.net/1822/40025
DOI10.1007/s00204-015-1582-x
ISSN0340-5761
Publisher versionhttp://link.springer.com/journal/204
Peer-Reviewedyes
AccessOpen access
Appears in Collections:ICVS - Artigos em revistas internacionais / Papers in international journals

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