Skip to main content
SpringerLink
Log in

An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication

  • Biologics
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

Amanita phalloides is one of the most toxic mushrooms worldwide, and it is involved in the majority of human fatal cases of mushroom poisoning. α-Amanitin, the most deleterious toxin of A. phalloides to humans, inhibits RNA polymerase II (RNAPII), causing hepatic and renal failure. Previously, we have shown that polymyxin B (polB) reverts α-amanitin inhibition of RNAPII, although it was not able to guarantee the full survival of α-amanitin-intoxicated mice or prevent α-amanitin pro-inflammatory effects. α-Amanitin is also a substrate of the organic-anion-transporting polypeptide 1B3 (OATP1B3) and Na(+)-taurocholate cotransporter polypeptide (NTCP) transporters. Therefore, in the present work, we used a combination of polB [(2.5 mg/kg intraperitoneal (i.p.)] with the anti-inflammatory and NTCP inhibitor drug, methylprednisolone (MP) (10 mg/kg i.p.), as an attempt to fully revert α-amanitin-induced toxicity (0.33 mg/kg i.p.) in CD-1 mice. Results showed that the administration of the polB + MP combination, 4 h after α-amanitin, led to the full survival of the intoxicated animals, with a significant attenuation of α-amanitin-induced renal and hepatic necrosis. Also, the combination polB + MP led to a decrease of aminotransferase plasma levels, of the renal myeloperoxidase activity and of renal inflammatory cell infiltrate promoted by α-amanitin, although not preventing any of the hepatic pro-inflammatory effect of the toxin. The obtained results indicate that this combination may represent an important and valuable therapeutic approach to be used against α-amanitin intoxication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

AP:

Alkaline phosphatase

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

MLD:

Minimum lethal dose

MPO:

Myeloperoxidase

NF-κB:

Nuclear factor kappa-B

NTCP:

Na(+)-taurocholate cotransporter polypeptide

OATP:

Organic-anion-transporting polypeptide

TMB:

3,3′,5,5′-tetramethylbenzidine

RNAPII:

RNA polymerase II

TNF-α:

Tumor necrosis factor-α.

References

  • Barbosa DJ, Capela JP, Oliveira JM, Silva R, Ferreira LM, Siopa F, Branco PS, Fernandes E, Duarte JA, de Lourdes Bastos M, Carvalho F (2012) Pro-oxidant effects of Ecstasy and its metabolites in mouse brain synaptosome. Br J Pharmacol 165(4b):1017–1033

    Article  Google Scholar 

  • Brown KE, Brunt EM, Heinecke JW (2001) Immunohistochemical detection of myeloperoxidase and its oxidation products in Kupffer cells of human liver. Am J Pathol 159(6):2081–2088

    Article  CAS  Google Scholar 

  • Dong Z, Ekins S, Polli JE (2013) Structure activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate co-transporting polypeptide (NTCP). Mol pharm 10(3):1008–1019

    Article  CAS  Google Scholar 

  • Feinberg SM, Feinberg AR, Pruzansky J, Fisherman EW (1957) Methylprednisolone (medrol), a potent new anti-inflammatory steroid: Therapeutic results in allergic diseases. J Am Med Assoc 165(12):1560–1562

    Article  CAS  Google Scholar 

  • Ferreira R, Vitorino R, Neuparth MJ, Appell H-J, Amado F, Duarte JA (2007) Cellular patterns of the atrophic response in murine soleus and gastrocnemius muscles submitted to simulated weightlessness. Eur J Appl Physiol 101(3):331–340

    Article  Google Scholar 

  • Fiume L, Marinozzi V, Nardi F (1969) The effects of amanitin poisoning on mouse kidney. Br J Exp Pathol 50(3):270–276

    CAS  PubMed  PubMed Central  Google Scholar 

  • Floersheim GL (1976) Antagonistic effects against single lethal doses of Amanita phalloides. Naunyn Schmiedebergs Arch Pharmacol 293(2):171–174

    Article  CAS  Google Scholar 

  • Garcia J, Costa VM, Carvalho A et al (2015a) Amanita phalloides poisoning: mechanisms of toxicity and treatment. Food Chem Toxicol 86:41–55

    Article  CAS  Google Scholar 

  • Garcia J, Costa VM, Carvalho AT et al (2015b) A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Arch Toxicol 89(12):2305–2323

    Article  CAS  Google Scholar 

  • Garcia J, Costa VM, Costa AE et al (2015c) Co-ingestion of amatoxins and isoxazoles-containing mushrooms and successful treatment: a case report. Toxicon 103:55–59

    Article  CAS  Google Scholar 

  • Gobe GC, Johnson DW (2007) Distal tubular epithelial cells of the kidney: Potential support for proximal tubular cell survival after renal injury. Int J Biochem Cell Biol 39(9):1551–1561

    Article  CAS  Google Scholar 

  • Gross S, Gammon ST, Moss BL et al (2009) Bioluminescence imaging of myeloperoxidase activity in vivo. Nat med 15(4):455–461

    Article  CAS  Google Scholar 

  • Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W (2017) Annual report of the American association of poison control centers’ national poison data system (NPDS): 34th annual report. Clin Toxicol (Phila) 55(10):1072–1252

    Article  Google Scholar 

  • Gundala S, Wells LD, Milliano MT, Talkad V, Luxon BA, Neuschwander-Tetri BA (2004) The hepatocellular bile acid transporter Ntcp facilitates uptake of the lethal mushroom toxin alpha-amanitin. Arch Toxicol 78(2):68–73

    Article  CAS  Google Scholar 

  • Jacek R, Elżbieta PJ, Andrzej K et al (2004) Successful treatment of a child with fulminant liver failure and coma caused by Amanita phalloides intoxication with albumin dialysis without liver transplantation. Pediatr Transplant 8(3):295–300

    Article  Google Scholar 

  • Kalač P (2009) Chemical composition and nutritional value of European species of wild growing mushrooms: a review. Food Chem 113(1):9–16

    Article  Google Scholar 

  • Kiberd BA, Young ID (1994) Modulation of glomerular structure and function in murine lupus nephritis by methylprednisolone and cyclophosphamide. J Lab Clin Med 124(4):496–506

    CAS  PubMed  Google Scholar 

  • Klein AS, Hart J, Brems JJ, Goldstein L, Lewin K, Busuttil RW (1989) Amanita poisoning: treatment and the role of liver transplantation. Am J Med 86(2):187–193

    Article  CAS  Google Scholar 

  • Krasnodebski M, Grat M, Holowko W et al (2016) Results of liver transplantation in patients with acute liver failure due to Amanita phalloides and paracetamol (acetaminophen) intoxication. Prz Gastroenterol 11(2):90–95

    CAS  PubMed  Google Scholar 

  • Leist M, Gantner F, Naumann H et al (1997) Tumor necrosis factor-induced apoptosis during the poisoning of mice with hepatotoxins. Gastroenterology 112(3):923–934

    Article  CAS  Google Scholar 

  • Letschert K, Faulstich H, Keller D, Keppler D (2006) Molecular characterization and inhibition of amanitin uptake into human hepatocytes. Toxicol Sci 91(1):140–149

    Article  CAS  Google Scholar 

  • Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193(1):265–275

    CAS  PubMed  Google Scholar 

  • Sadikot RT, Jansen ED, Blackwell TR et al (2001) High-dose dexamethasone accentuates nuclear factor-kappa b activation in endotoxin-treated mice. Am J Respir Crit Care Med 164(5):873–878

    Article  CAS  Google Scholar 

  • Schenk-Jaeger KM, Rauber-Luthy C, Bodmer M, Kupferschmidt H, Kullak-Ublick GA, Ceschi A (2012) Mushroom poisoning: a study on circumstances of exposure and patterns of toxicity. Eur J Intern Med 23(4):e85–e91

    Article  Google Scholar 

  • Su L, Li N, Tang H et al (2018) Kupffer cell-derived TNF-α promotes hepatocytes to produce CXCL1 and mobilize neutrophils in response to necrotic cells. Cell Death Dis 9(3):323

    Article  Google Scholar 

  • Temple A, Yen T-Y, Gronert S (2006) Identification of specific protein carbonylation sites in model oxidations of human serum albumin. J Am Soc Mass Spectrom 17(8):1172–1180

    Article  CAS  Google Scholar 

  • Vetter J (1998) Toxins of Amanita phalloides. Toxicon 36(1):13–24

    Article  CAS  Google Scholar 

  • Wieland T, Faulstich H (1978) Amatoxins, phallotoxins, phallolysin, and antamanide: the biologically active components of poisonous Amanita mushrooms. CRC Crit Rev Biochem 5(3):185–260

    Article  CAS  Google Scholar 

  • Yan LJ, Traber MG, Kobuchi H, Matsugo S, Tritschler HJ, Packer L (1996) Efficacy of hypochlorous acid scavengers in the prevention of protein carbonyl formation. Arch Biochem Biophys 327(2):330–334

    Article  CAS  Google Scholar 

  • You Y, Qin Y, Lin X et al (2015) Methylprednisolone attenuates lipopolysaccharide-induced Fractalkine expression in kidney of Lupus-prone MRL/lpr mice through the NF-kappa B pathway. BMC Nephrol 16:148

    Article  Google Scholar 

  • Zheleva A, Tolekova A, Zhelev M, Uzunova V, Platikanova M, Gadzheva V (2007) Free radical reactions might contribute to severe alpha amanitin hepatotoxicity—a hypothesis. Med Hypotheses 69(2):361–367

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We greatly acknowledge Dra Laura Pereira and Master Bárbara Duarte for their technical assistance in the determination of plasma parameters. VMC thanks Fundação para a Ciência e Tecnologia (FCT) for her grant SFRH/BPD/110001/2015. This work was supported by FEDER funds through the Operational Programme for Competitiveness Factors—COMPETE and by national funds by the Fundação para a Ciência e Tecnologia (FCT) within the project “PTDC/DTP-FTO/4973/2014– POCI-01-0145-FEDER- 016545”.

Author information

Authors and Affiliations

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

    Juliana Garcia, Vera Marisa Costa, Daniela Ferreira Rodrigues, Maria de Lourdes Bastos & Félix Carvalho

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

    Antonio Bovolini & José Alberto Duarte

Authors
  1. Juliana Garcia
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vera Marisa Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Antonio Bovolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José Alberto Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniela Ferreira Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria de Lourdes Bastos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Félix Carvalho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Juliana Garcia or Félix Carvalho.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garcia, J., Costa, V.M., Bovolini, A. et al. An effective antidotal combination of polymyxin B and methylprednisolone for α-amanitin intoxication. Arch Toxicol 93, 1449–1463 (2019). https://doi.org/10.1007/s00204-019-02426-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00204-019-02426-5

Keywords

Search

Navigation