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

  • Molecular Toxicology
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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.

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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.

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Authors and Affiliations

  1. UCIBIO/REQUIMTE-Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto, Rua José Viterbo Ferreira no 228, 4050-313, Porto, Portugal

    Juliana Garcia, Vera Marisa Costa, Marcelo D. Arbo, Teresa Baltazar, Ricardo Jorge Dinis-Oliveira, Maria de Lourdes Bastos & Félix Carvalho

  2. Department of Cell and Molecular Biology, Computational and Systems Biology, Biomedical Center, Uppsala University, Box 596, 751 24, Uppsala, Sweden

    Alexandra T. P. Carvalho & Daniel F. A. R. Dourado

  3. School of Health Sciences, Life and Health Sciences Research Institute (ICVS), University of Minho, Braga, Portugal

    Ricardo Silvestre

  4. ICVS/3B’s-PT Government Associate Laboratory, Braga, Guimarães, Portugal

    Ricardo Silvestre

  5. Faculty of Sport, CIAFEL, University of Porto, Porto, Portugal

    José Alberto Duarte

  6. Department of Legal Medicine and Forensic Sciences, Faculty of Medicine, University of Porto, Porto, Portugal

    Ricardo Jorge Dinis-Oliveira

  7. Department of Sciences, IINFACTS-Institute of Research and Advanced Training in Health Sciences and Technologies, Advanced Institute of Health Sciences–North (ISCS-N), CESPU, CRL, Gandra, Portugal

    Ricardo Jorge Dinis-Oliveira

  8. CIMO/School of Agriculture, Polytechnic Institute of Bragança, Campus de Santa Apolónia Apartado 1172, 5301-854, Bragança, Portugal

    Paula Baptista

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  1. Juliana Garcia
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Correspondence to Juliana Garcia or Félix Carvalho.

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Garcia, J., Costa, V.M., Carvalho, A.T.P. et al. A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Arch Toxicol 89, 2305–2323 (2015). https://doi.org/10.1007/s00204-015-1582-x

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