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Effets ototoxiques du toluène et ses spécificités métaboliques (phase I et II) chez le rat et le cobaye

Abstract : The hearing of rats, contrary to that of guinea pigs, is vulnerable to toluene exposure by inhalation. The first aim of this thesis was to evaluate the hepatic metabolism impact on toluene-induced ototoxicity. The second aim was to improve the understanding of the protective mechanisms developed by guinea pig to resist toluene intoxication. The oxidative and conjugate pathways involved in toluene metabolism were induced by 5-ethyl-5-phenyl-2,4,6 (1H, 3H, 5H)-pyrimidinetrione (Phenobarbital) (50 mg/kg: 5 d/w., 4 w.), or depressed by inhibitors such as (alpha S,5S)-alpha-amino-3-chloro-4,5-dihydro-5-isoxazoleacetic acid (acivicin) (5 mg/kg: 2 d/w, 4w.) for the ? glutamyltransferase and 2-diethylaminoethyl 2,2-diphenylvalerate: (SKF 525A) (50 mg/kg: 2 d/w., 4 w.) for the cytochromes P450 (CYP450). The modifications of the hepatic metabolism clearly showed that the blood concentration of toluene was responsible for the solvent ototoxicity, pushing the cysteine S-conjugates into the background. On the other hand, the inhibition program of the CYP450 showed that the inhibition of both detoxification pathways is very difficult. The metabolism is capable of compensating the inhibition of the major pathway in our experimental context. For the first time, toluene-induced hearing loss was assessed in the guinea pig having depressed CYP450. The guinea pigs suffered from spiral fibre rather than hair cell losses. These histological findings pleaded in favour of neurotoxic effects induced by solvent exposures. Within the organ of Corti, the presence of melanin could also constitute a barrier against toluene intoxication. At last, an antioxidant molecule such as glutathion, which is largely present in cochlea, could play a major role against solvent intoxication.
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Delphine Waniusiow. Effets ototoxiques du toluène et ses spécificités métaboliques (phase I et II) chez le rat et le cobaye. Sciences pharmaceutiques. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10020⟩. ⟨tel-01748488⟩



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