title: Reduced systemic toxicity and preserved vestibular toxicity following co-treatment with nitriles and CYP2E1 inhibitors: a mouse model for hair cell loss.
abstract: Several nitriles, including allylnitrile and cis-crotononitrile, have been shown to be ototoxic and cause hair cell degeneration in the auditory and vestibular sensory epithelia of mice. However, these nitriles can also be lethal due in large part to the microsomal metabolic release of cyanide, which is mostly dependent on the activity of the 2E1 isoform of the cytochrome P450 (CYP2E1). In this study, we co-administered mice with a nitrile and, to reduce their lethal effects, a selective CYP2E1 inhibitor: diallylsulfide (DAS) or trans-1,2-dichloroethylene (TDCE). Both in female 129S1/SvImJ (129S1) mice co-treated with DAS and cis-crotononitrile and in male RjOrl:Swiss/CD-1 (Swiss) mice co-treated with TDCE and allylnitrile, the nitrile caused a dose-dependent loss of vestibular function, as assessed by a specific behavioral test battery, and of hair cells, as assessed by hair bundle counts using scanning electron microscopy. In the experiments, the CYP2E1 inhibitors provided significant protection against the lethal effects of the nitriles and did not diminish the vestibular toxicity as assessed by behavioral effects in comparison to animals receiving no inhibitor. Additional experiments using a single dose of allylnitrile demonstrated that TDCE does not cause hair cell loss on its own and does not modify the vestibular toxicity of the nitrile in either male or female 129S1 mice. In all the experiments, high vestibular dysfunction scores in the behavioral test battery predicted extensive to complete loss of hair cells in the utricles. This provides a means of selecting animals for subsequent studies of vestibular hair cell regeneration or replacement.
authors.affiliation: Departament de Ciències Fisiològiques II, Universitat de Barcelona, Feixa Llarga s/n, 08907 L'Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Saldaña-Ruíz
authors.forename: Pere
authors.initials: P
authors.lastname: Boadas-Vaello
authors.forename: Lara
authors.initials: L
authors.lastname: Sedó-Cabezón
authors.forename: Jordi
authors.initials: J
authors.lastname: Llorens
mesh_terms: D000498:Allyl Compounds / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D003638:Deafness / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D018069:Hair Cells, Vestibular / Q000187:drug effects / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008855:Microscopy, Electron, Scanning; D009570:Nitriles / Q000633:toxicity*; D013440:Sulfides / Q000633:toxicity*; D014724:Vestibular Function Tests; D014722:Vestibule, Labyrinth / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure
chemical_list: D000498:Allyl Compounds; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D009570:Nitriles; D013440:Sulfides; C031103:crotononitrile; C015660:allyl cyanide; C038491:allyl sulfide