Please use this identifier to cite or link to this item: http://hdl.handle.net/2445/65628
Title: Vestibulotoxic properties of potential metabolites of allylnitrile
Author: Rúa, Federico
Buffard, Mélodie
Sedó Cabezón, Lara
Hernández-Mir, Gerard
Torre, Aurélien de la
Saldaña-Ruíz, Sandra
Chabbert, Christian
Bayona i Termens, Josep Maria
Messeguer i Peypoch, Àngel, 1946-
Llorens i Baucells, Jordi
Keywords: Nitrils
Toxicologia
Animals de laboratori
Cervell
Nitriles
Toxicology
Laboratory animals
Brain
Issue Date: 1-Sep-2013
Publisher: Academic Press
Abstract: This study addressed the hypothesis that epoxidation of the double bond in allylnitrile mediates its vestibular toxicity, directly or after subsequent metabolism by epoxide hydrolases. The potential metabolites 3,4-epoxybutyronitrile and 3,4-dihydroxybutyronitrile were synthesized and characterized. In aqueous solutions containing sodium or potassium ions, 3,4-epoxybutyronitrile rearranged to 4-hydroxybut-2-enenitrile, and this compound was also isolated for study. Male adult Long-Evans rats were exposed to allylnitrile or 3,4-epoxybutyronitrile by bilateral transtympanic injection, and vestibular toxicity was assessed using a behavioral test battery and scanning electron microscopy (SEM) observation of the sensory epithelia. Overt vestibular toxicity was caused by 3,4-epoxybutyronitrile at 0.125 mmol/ear and by allylnitrile in some animals at 0.25 mmol/ear. Additional rats were exposed by unilateral transtympanic injection. In these studies, behavioral evidences and SEM observations demonstrated unilateral vestibular toxicity after 0.125 mmol of 3,4-epoxybutyronitrile and bilateral vestibular toxicity after 0.50 mmol of allylnitrile. However, 0.25 mmol of allylnitrile did not cause vestibular toxicity. Unilateral administration of 0.50 mmol of 3,4-dihydroxybutyronitrile or 4-hydroxybut-2-enenitrile caused no vestibular toxicity. The four compounds were also evaluated in the mouse utricle explant culture model. In 8-h exposure experiments, hair cells completely disappeared after 3,4-epoxybutyronitrile at concentrations of 325 or 450μM but not at concentrations of 150μM or lower. In contrast, no difference from controls was recorded in utricles exposed to 450μM or 1.5mM of allylnitrile, 3,4-dihydroxybutyronitrile, or 4-hydroxybut-2-enenitrile. Taken together, the present data support the hypothesis that 3,4-epoxybutyronitrile is the active metabolite of allylnitrile for vestibular toxicity.
Note: Versió postprint del document publicat a: http://dx.doi.org/10.1093/toxsci/kft127
It is part of: Toxicological Sciences, 2013, vol. 135, num. 1, p. 182-192
Related resource: http://dx.doi.org/10.1093/toxsci/kft127
URI: http://hdl.handle.net/2445/65628
ISSN: 1096-6080
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Centres Científics i Tecnològics de la Universitat de Barcelona (CCiTUB))
Articles publicats en revistes (Ciències Fisiològiques)

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