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dc.contributor.authorBoadas-Vaello, Pere-
dc.contributor.authorJover Comas, Eric-
dc.contributor.authorDíez Padrisa, Núria-
dc.contributor.authorBayona Termens, Josep María-
dc.contributor.authorLlorens, Jordi-
dc.date.accessioned2009-02-05T10:29:34Z-
dc.date.available2009-02-05T10:29:34Z-
dc.date.issued2007-08-07-
dc.identifier.citationToxicology and Applied Pharmacology 225(3): 310-317 (2007)en_US
dc.identifier.issn0041-008x-
dc.identifier.urihttp://hdl.handle.net/10261/10329-
dc.description8 pages, 4 figures.-- PMID: 17878057 [PubMed].-- Printed version published on Dec 15, 2007.en_US
dc.descriptionParts of this work were presented at the 43rd Inner Ear Biology Workshop, Montpellier, France, September 2006, and the 11th Meeting of the International Neurotoxicology Association, Pacific Grove, California, USA, June 2007.-
dc.description.abstractSeveral alkylnitriles are toxic to sensory systems, including the vestibular system, through yet undefined mechanisms. This study addressed the hypothesis that the vestibular toxicity of cis-crotononitrile depends on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null female mice were exposed to cis-crotononitrile at 0, 2, 2.25 or 2.5 mmol/kg (p.o.) in either a baseline condition or following exposure to 1% acetone in drinking water to induce CYP2E1 expression. The exposed animals were assessed for vestibular toxicity using a behavioral test battery and through surface observation of the vestibular sensory epithelia by scanning electron microscopy. In parallel groups, concentrations of cis-crotononitrile and cyanide were assessed in whole blood. Contrary to our hypothesis, CYP2E1-null mice were slightly more susceptible to the vestibular toxicity of ciscrotononitrile than were control 129S1 mice. Similarly, rather than enhance vestibular toxicity, acetone pretreatment actually reduced it slightly in 129S1 controls, although not in CYP2E1-null mice. In addition, significant differences in mortality were recorded, with the greatest mortality occurring in 129S1 mice after acetone pretreatment. The highest mortality recorded in the 129S1 + acetone mice was associated with the lowest blood concentrations of cis-crotononitrile and the highest concentrations of cyanide at 6 h after nitrile exposure, the time when deaths were initially recorded. We conclude that cis-crotononitrile is a CYP2E1 substrate as hypothesized, but that CYP2E1-mediated metabolism of this nitrile is not necessary for vestibular toxicity; rather, this metabolism constitutes a major pathway for cyanide release and subsequent lethality.en_US
dc.description.sponsorshipWe thank Frank J. Gonzalez (NIH, Bethesda, USA) for generously providing the CYP2E1-null mice and Joaquim Messeguer (CSIC, Barcelona, Spain) for help with the distillation of cis-crotononitrile. This work was supported by grants BFU2006-00343/BFI and CGL2005-02846/BOS from the Spanish Ministry of Education and Science / E.U. FEDER and 2005SGR00022 from Generalitat of Catalonia. The SEM studies were performed at the Serveis Científico-Tècnics (Scientific–Technical Services) of the University of Barcelona.en_US
dc.format.extent19968 bytes-
dc.format.mimetypeapplication/msword-
dc.language.isoengen_US
dc.publisherElsevieren_US
dc.rightsclosedAccessen_US
dc.subjectOtotoxicityen_US
dc.subjectHair cell degenerationen_US
dc.subjectNitrileen_US
dc.subjectVestibular dysfunctionen_US
dc.subjectCYP2E1-mediated metabolismen_US
dc.subjectCyanideen_US
dc.titleDifferential role of CYP2E1-mediated metabolism in the lethal and vestibulotoxic effects of cis-crotononitrile in the mouseen_US
dc.typeArtículoen_US
dc.identifier.doi10.1016/j.taap.2007.07.014-
dc.description.peerreviewedPeer revieweden_US
dc.relation.publisherversionhttp://dx.doi.org/10.1016/j.taap.2007.07.014en_US
dc.identifier.e-issn1096-0333-
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