title: Vestibulotoxic properties of potential metabolites of allylnitrile.
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.
authors.affiliation: Departament de Nanotecnologia Química i Biomolecular, Institut de Química Avançada de Catalunya-CSIC, 08034 Barcelona, Catalunya, Spain.
authors.forename: Federico
authors.initials: F
authors.lastname: Rúa
authors.forename: Mélodie
authors.initials: M
authors.lastname: Buffard
authors.forename: Lara
authors.initials: L
authors.lastname: Sedó-Cabezón
authors.forename: Gerard
authors.initials: G
authors.lastname: Hernández-Mir
authors.forename: Aurélien
authors.initials: A
authors.lastname: de la Torre
authors.forename: Sandra
authors.initials: S
authors.lastname: Saldaña-Ruíz
authors.forename: Christian
authors.initials: C
authors.lastname: Chabbert
authors.forename: Josep M
authors.initials: JM
authors.lastname: Bayona
authors.forename: Angel
authors.initials: A
authors.lastname: Messeguer
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
mesh_terms: D000818:Animals; D001711:Biotransformation; D004852:Epoxy Compounds / Q000633:toxicity*; D005260:Female; D008297:Male; D051379:Mice; D009570:Nitriles / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D020318:Rats, Long-Evans; D014722:Vestibule, Labyrinth / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure
chemical_list: D004852:Epoxy Compounds; D009570:Nitriles; C015660:allyl cyanide
keywords: 3,4-epoxybutyronitrile; hair cell.; nitrile; ototoxicity; vestibular toxicity; xenobiotic metabolism