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Differential role of CYP2E1-mediated metabolism in the lethal and vestibulotoxic effects of cis-crotononitrile in the mouse

AutorBoadas-Vaello, Pere; Jover Comas, Eric; Díez Padrisa, Núria; Bayona Termens, Josep María; Llorens, Jordi
Palabras claveOtotoxicity
Hair cell degeneration
Vestibular dysfunction
CYP2E1-mediated metabolism
Fecha de publicación7-ago-2007
CitaciónToxicology and Applied Pharmacology 225(3): 310-317 (2007)
ResumenSeveral 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.
Descripción8 pages, 4 figures.-- PMID: 17878057 [PubMed].-- Printed version published on Dec 15, 2007.
Parts 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.
Versión del editorhttp://dx.doi.org/10.1016/j.taap.2007.07.014
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