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

2015Journal article Open access
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dc.contributor.authorGarcia, Juliana
dc.contributor.authorCosta, Vera M.
dc.contributor.authorCarvalho, Alexandra T.P.
dc.contributor.authorSilvestre, Ricardo
dc.contributor.authorDuarte, José A.
dc.contributor.authorDourado, Daniel F.A.R.
dc.contributor.authorArbo, Marcelo D.
dc.contributor.authorBaltazar, Teresa
dc.contributor.authorDinis-Oliveira, Ricardo Jorge
dc.contributor.authorBaptista, Paula
dc.contributor.authorBastos, Maria de Lourdes
dc.contributor.authorCarvalho, Félix
dc.date.accessioned2018-02-19T10:00:00Z
dc.date.accessioned2018-03-01T16:04:46Z
dc.date.accessioned2018-03-05T09:19:02Z
dc.date.available2018-01-19T10:00:00Z
dc.date.available2018-03-01T16:04:46Z
dc.date.available2018-03-05T09:19:02Z
dc.date.issued2015
dc.description.abstractAmanita 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.en_EN
dc.description.sponsorshipJuliana 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.
dc.description.versioninfo:eu-repo/semantics/publishedVersionen_EN
dc.identifier.citationGarcia, Juliana; Costa, Vera Marisa; Carvalho, Alexandra T.P.; Silvestre, Ricardo; Duarte, José Alberto; Dourado, Daniel F.A.R.; Arbo, Marcelo D.; Baltazar, Teresa; Dinis-Oliveira, Ricardo Jorge; Baptista, Paula; Bastos, Maria de Lourdes; Carvalho, Félix (2015). A breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin B. Archives of Toxicology. ISSN 0340-5761. 89, p. 2305-2323en_EN
dc.identifier.doi10.1007/s00204-015-1582-xen_EN
dc.identifier.issn0340-5761
dc.identifier.urihttp://hdl.handle.net/10198/16102
dc.language.isoeng
dc.peerreviewedyesen_EN
dc.relationPTDC/DTP/FTO/4973/2014
dc.relationPoisoning the heart with anticancer drugs: is metabolic bioactivation or aging promotion the link to the cardiotoxicity of anticancer drugs New early putative biomarkers of cardiac damage for an earlier therapeutic approach
dc.subjectKidneyen_EN
dc.subjectLiveren_EN
dc.subjectPolymyxin Ben_EN
dc.subjectRNA polymerase IIen_EN
dc.subjectα-Amanitinen_EN
dc.titleA breakthrough on Amanita phalloides poisoning: an effective antidotal effect by polymyxin Ben_EN
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitlePoisoning the heart with anticancer drugs: is metabolic bioactivation or aging promotion the link to the cardiotoxicity of anticancer drugs New early putative biomarkers of cardiac damage for an earlier therapeutic approach
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBD%2F74979%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/SFRH/SFRH%2FBPD%2F63746%2F2009/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBPD%2F110001%2F2015/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/COMPETE/PEst-C%2FEQB%2FLA0006%2F2013/PT
oaire.fundingStreamSFRH
oaire.fundingStreamSFRH
oaire.fundingStreamCOMPETE
person.familyNameBaptista
person.givenNamePaula
person.identifier.ciencia-id7D11-FE1E-CD0F
person.identifier.orcid0000-0001-6331-3731
person.identifier.scopus-author-id14051688000
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccessen_EN
rcaap.typearticleen_EN
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relation.isAuthorOfPublication.latestForDiscovery3f35226a-b17a-4f7d-8da1-3297105cbfe9
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