Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse

This study addressed the hypothesis that the vestibular or lethal toxicities of allylnitrile depend on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null male mice were exposed to allylnitrile at doses of 0, 0.5, 0.75, or 1.0 mmol/kg (po), following exposure to drinking water with 0 or...

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Autores: Boadas i Vaello, Pere, Jover, Eric, Saldaña-Ruíz, Sandra, Soler-Martín, Carla, Chabbert, Christian, Bayona i Termens, Josep Maria, Llorens i Baucells, Jordi
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2009
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/48272
Acceso en línea:https://hdl.handle.net/2445/48272
Access Level:acceso abierto
Palabra clave:Productes químics
Nitrils
Animals
Toxicologia
Equilibri (Fisiologia)
Vertigen
Malalties de l'orella
Chemical products
Nitriles
Toxicology
Equilibrium (Physiology)
Vertigo
Ear diseases
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network_name_str España
repository_id_str
spelling Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouseBoadas i Vaello, PereJover, EricSaldaña-Ruíz, SandraSoler-Martín, CarlaChabbert, ChristianBayona i Termens, Josep MariaLlorens i Baucells, JordiProductes químicsNitrilsAnimalsToxicologiaEquilibri (Fisiologia)VertigenMalalties de l'orellaChemical productsNitrilesAnimalsToxicologyEquilibrium (Physiology)VertigoEar diseasesThis study addressed the hypothesis that the vestibular or lethal toxicities of allylnitrile depend on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null male mice were exposed to allylnitrile at doses of 0, 0.5, 0.75, or 1.0 mmol/kg (po), following exposure to drinking water with 0 or 1% acetone, which induces CYP2E1 expression. Induction of CYP2E1 activity by acetone in 129S1 mice and lack of activity in null mice was confirmed in liver microsomes. Vestibular toxicity was assessed using a behavioral test battery and illustrated by scanning electron microscopy observation of the sensory epithelia. In parallel groups, concentrations of allylnitrile and cyanide were assessed in blood after exposure to 0.75 mmol/kg of allylnitrile. Following allylnitrile exposure, mortality was lower in CYP2E1-null than in 129S1 mice, and increased after acetone pretreatment only in 129S1 mice. This increase was associated with higher blood concentrations of cyanide. In contrast, no consistent differences were recorded in vestibular toxicity between 129S1 and CYP2E1-null mice, and between animals pretreated with acetone or not. Additional experiments evaluated the effect on the toxicity of 1.0 mmol/kg allylnitrile of the nonselective P450 inhibitor, 1-aminobenzotriazole, the CYP2E1-inhibitor, diallylsulfide, and the CYP2A5 inhibitor, methoxsalen. In 129S1 mice, aminobenzotriazole decreased both mortality and vestibular toxicity, whereas diallylsulfide decreased mortality only. In CYP2E1-null mice, aminobenzotriazole and methoxsalen, but not diallylsulfide, blocked allylnitrile-induced vestibular toxicity. We conclude that CYP2E1-mediated metabolism of allylnitrile leads to cyanide release and acute mortality, probably through α-carbon hydroxylation, and hypothesize that epoxidation of the β-γ double bond by CYP2A5 mediates vestibular toxicity.Academic Press2009info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersionapplication/pdfhttps://hdl.handle.net/2445/48272Articles publicats en revistes (Ciències Fisiològiques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésVersió postprint del document publicat a: http://dx.doi.org/10.1093/toxsci/kfn233Toxicological Sciences, 2009, vol. 107, num. 2, p. 461-472http://dx.doi.org/10.1093/toxsci/kfn233(c) Academic Press, 2009info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/482722026-05-27T06:46:51Z
dc.title.none.fl_str_mv Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
title Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
spellingShingle Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
Boadas i Vaello, Pere
Productes químics
Nitrils
Animals
Toxicologia
Equilibri (Fisiologia)
Vertigen
Malalties de l'orella
Chemical products
Nitriles
Animals
Toxicology
Equilibrium (Physiology)
Vertigo
Ear diseases
title_short Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
title_full Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
title_fullStr Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
title_full_unstemmed Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
title_sort Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
dc.creator.none.fl_str_mv Boadas i Vaello, Pere
Jover, Eric
Saldaña-Ruíz, Sandra
Soler-Martín, Carla
Chabbert, Christian
Bayona i Termens, Josep Maria
Llorens i Baucells, Jordi
author Boadas i Vaello, Pere
author_facet Boadas i Vaello, Pere
Jover, Eric
Saldaña-Ruíz, Sandra
Soler-Martín, Carla
Chabbert, Christian
Bayona i Termens, Josep Maria
Llorens i Baucells, Jordi
author_role author
author2 Jover, Eric
Saldaña-Ruíz, Sandra
Soler-Martín, Carla
Chabbert, Christian
Bayona i Termens, Josep Maria
Llorens i Baucells, Jordi
author2_role author
author
author
author
author
author
dc.subject.none.fl_str_mv Productes químics
Nitrils
Animals
Toxicologia
Equilibri (Fisiologia)
Vertigen
Malalties de l'orella
Chemical products
Nitriles
Animals
Toxicology
Equilibrium (Physiology)
Vertigo
Ear diseases
topic Productes químics
Nitrils
Animals
Toxicologia
Equilibri (Fisiologia)
Vertigen
Malalties de l'orella
Chemical products
Nitriles
Animals
Toxicology
Equilibrium (Physiology)
Vertigo
Ear diseases
description This study addressed the hypothesis that the vestibular or lethal toxicities of allylnitrile depend on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null male mice were exposed to allylnitrile at doses of 0, 0.5, 0.75, or 1.0 mmol/kg (po), following exposure to drinking water with 0 or 1% acetone, which induces CYP2E1 expression. Induction of CYP2E1 activity by acetone in 129S1 mice and lack of activity in null mice was confirmed in liver microsomes. Vestibular toxicity was assessed using a behavioral test battery and illustrated by scanning electron microscopy observation of the sensory epithelia. In parallel groups, concentrations of allylnitrile and cyanide were assessed in blood after exposure to 0.75 mmol/kg of allylnitrile. Following allylnitrile exposure, mortality was lower in CYP2E1-null than in 129S1 mice, and increased after acetone pretreatment only in 129S1 mice. This increase was associated with higher blood concentrations of cyanide. In contrast, no consistent differences were recorded in vestibular toxicity between 129S1 and CYP2E1-null mice, and between animals pretreated with acetone or not. Additional experiments evaluated the effect on the toxicity of 1.0 mmol/kg allylnitrile of the nonselective P450 inhibitor, 1-aminobenzotriazole, the CYP2E1-inhibitor, diallylsulfide, and the CYP2A5 inhibitor, methoxsalen. In 129S1 mice, aminobenzotriazole decreased both mortality and vestibular toxicity, whereas diallylsulfide decreased mortality only. In CYP2E1-null mice, aminobenzotriazole and methoxsalen, but not diallylsulfide, blocked allylnitrile-induced vestibular toxicity. We conclude that CYP2E1-mediated metabolism of allylnitrile leads to cyanide release and acute mortality, probably through α-carbon hydroxylation, and hypothesize that epoxidation of the β-γ double bond by CYP2A5 mediates vestibular toxicity.
publishDate 2009
dc.date.none.fl_str_mv 2009
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/48272
url https://hdl.handle.net/2445/48272
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: http://dx.doi.org/10.1093/toxsci/kfn233
Toxicological Sciences, 2009, vol. 107, num. 2, p. 461-472
http://dx.doi.org/10.1093/toxsci/kfn233
dc.rights.none.fl_str_mv (c) Academic Press, 2009
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Academic Press, 2009
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Academic Press
publisher.none.fl_str_mv Academic Press
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Fisiològiques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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