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Archives of Toxicology

, Volume 89, Issue 12, pp 2305–2323 | Cite as

A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B

  • Juliana Garcia
  • Vera Marisa Costa
  • Alexandra T. P. Carvalho
  • Ricardo Silvestre
  • José Alberto Duarte
  • Daniel F. A. R. Dourado
  • Marcelo D. Arbo
  • Teresa Baltazar
  • Ricardo Jorge Dinis-Oliveira
  • Paula Baptista
  • Maria de Lourdes Bastos
  • Félix Carvalho
Molecular Toxicology

Abstract

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

Keywords

α-Amanitin RNA polymerase II Polymyxin B Liver Kidney 

Notes

Acknowledgments

Juliana Garcia, Vera Marisa Costa, Ricardo Dinis-Oliveira and Ricardo Silvestre thank FCT—Foundation for Science and Technology—for their PhD grant (SFRH/BD/74979/2010), Post-doc grants (SFRH/BPD/63746/2009 and SFRH/BPD/110001/2015) and Investigator grants (IF/01147/2013) and (IF/00021/2014), respectively. This work was supported by the Fundação para a Ciência e Tecnologia (FCT) – project PTDC/DTPFTO/4973/2014 – and the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia) through project Pest-C/EQB/LA0006/2013.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Juliana Garcia
    • 1
  • Vera Marisa Costa
    • 1
  • Alexandra T. P. Carvalho
    • 2
  • Ricardo Silvestre
    • 3
    • 4
  • José Alberto Duarte
    • 5
  • Daniel F. A. R. Dourado
    • 2
  • Marcelo D. Arbo
    • 1
  • Teresa Baltazar
    • 1
  • Ricardo Jorge Dinis-Oliveira
    • 1
    • 6
    • 7
  • Paula Baptista
    • 8
  • Maria de Lourdes Bastos
    • 1
  • Félix Carvalho
    • 1
  1. 1.UCIBIO/REQUIMTE-Laboratory of Toxicology, Department of Biological Sciences, Faculty of PharmacyUniversity of PortoPortoPortugal
  2. 2.Department of Cell and Molecular Biology, Computational and Systems Biology, Biomedical CenterUppsala UniversityUppsalaSweden
  3. 3.School of Health Sciences, Life and Health Sciences Research Institute (ICVS)University of MinhoBragaPortugal
  4. 4.ICVS/3B’s-PT Government Associate LaboratoryBraga, GuimarãesPortugal
  5. 5.Faculty of Sport, CIAFELUniversity of PortoPortoPortugal
  6. 6.Department of Legal Medicine and Forensic Sciences, Faculty of MedicineUniversity of PortoPortoPortugal
  7. 7.Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and TechnologiesAdvanced Institute of Health Sciences–North (ISCS-N), CESPU, CRLGandraPortugal
  8. 8.CIMO/School of Agriculture, Polytechnic Institute of BragançaBragançaPortugal

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