Differential role of CYP2E1-mediated metabolism in the lethal and vestibulotoxic effects of cis-crotononitrile in the mouse.
Several 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 cis-crotononitrile 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.
Boadas-Vaello
Pere
P
Departament de Ciències Fisiològiques II, Universitat de Barcelona - IDIBELL, Feixa Llarga s/n, 08907, Hospitalet de Llobregat, Spain.
Jover
Eric
E
Díez-Padrisa
Núria
N
Bayona
Josep M
JM
Llorens
Jordi
J
D000096:Acetone / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003486:Cyanides / Q000378:metabolism / Q000493:pharmacokinetics; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D009570:Nitriles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors; D014724:Vestibular Function Tests; D014722:Vestibule, Labyrinth / Q000187:drug effects* / Q000473:pathology
D003486:Cyanides; D009570:Nitriles; D000096:Acetone; C031103:crotononitrile; D019392:Cytochrome P-450 CYP2E1