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A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B
Univ Porto, Fac Pharm, Dept Biol Sci, UCIBIO REQUIMTE Lab Toxicol, P-4050313 Oporto, Portugal..
Univ Porto, Fac Pharm, Dept Biol Sci, UCIBIO REQUIMTE Lab Toxicol, P-4050313 Oporto, Portugal..
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Univ Minho, Sch Hlth Sci, Life & Hlth Sci Res Inst ICVS, Braga, Portugal.;ICVS 3Bs PT Govt Associate Lab, Braga, Guimaraes, Portugal..
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2015 (English)In: Archives of Toxicology, ISSN 0340-5761, E-ISSN 1432-0738, Vol. 89, no 12, 2305-2323 p.Article in journal (Refereed) PublishedText
Abstract [en]

Amanita phalloides is responsible for more than 90 % of mushroom-related fatalities, and no effective antidote is available. alpha-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 alpha-amanitin, polymyxin B. The results show that polymyxin B potentially binds to RNAP II in the same interface of alpha-amanitin, preventing the toxin from binding to RNAP II. In vivo, the inhibition of the mRNA transcripts elicited by alpha-amanitin was efficiently reverted by polymyxin B in the kidneys. Moreover, polymyxin B significantly decreased the hepatic and renal alpha-amanitin-induced injury as seen by the histology and hepatic aminotransferases plasma data. In the survival assay, all animals exposed to alpha-amanitin died within 5 days, whereas 50 % survived up to 30 days when polymyxin B was administered 4, 8, and 12 h post-alpha-amanitin. Moreover, a single dose of polymyxin B administered concomitantly with alpha-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 alpha-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.

Place, publisher, year, edition, pages
2015. Vol. 89, no 12, 2305-2323 p.
Keyword [en]
alpha-Amanitin, RNA polymerase II, Polymyxin B, Liver, Kidney
National Category
Pharmacology and Toxicology
URN: urn:nbn:se:uu:diva-272121DOI: 10.1007/s00204-015-1582-xISI: 000366155200010PubMedID: 26385100OAI: oai:DiVA.org:uu-272121DiVA: diva2:893173
EU, European Research Council
Available from: 2016-01-12 Created: 2016-01-12 Last updated: 2016-01-12Bibliographically approved

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