Allylnitrile metabolism by CYP2E1 and other CYPs leads to distinct lethal and vestibulotoxic effects in the mouse
| Autor: | Sandra Saldaña-Ruíz, Christian Chabbert, Pere Boadas-Vaello, Eric Jover, Jordi Llorens, Josep M. Bayona, Carla Soler-Martín |
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| Přispěvatelé: | Hamel, Christian, Departament de Ciencies Fisiologiques II, Universitat de Barcelona (UB), Departament de Química Ambiental, Institut de Diagnòstic Ambiental i Estudis de l'Aigua ? CSIC, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2009 |
| Předmět: |
MESH: Epoxy Compounds
Equilibrium (Physiology) MESH: Solvents MESH: Aryl Hydrocarbon Hydroxylases Pharmacology Toxicology MESH: Mice Knockout MESH: Dose-Response Relationship Drug Cytochrome P-450 CYP2A6 Hydroxylation Mice chemistry.chemical_compound MESH: Acetone 0302 clinical medicine Cytochrome P-450 Enzyme System Ear diseases MESH: Allyl Compounds MESH: Behavior Animal Cytochrome P-450 Enzyme Inhibitors MESH: Animals Enzyme Inhibitors Mice Knockout 0303 health sciences Behavior Animal MESH: Indicators and Reagents Cytochrome P-450 CYP2E1 CYP2E1 MESH: Nitriles 3. Good health Allyl Compounds Cytochrome P-450 CYP2E1 Inhibitors Nitrils Vestibular Diseases Biochemistry MESH: Enzyme Inhibitors Toxicity MESH: Cytochrome P-450 Enzyme System Vertigo [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Aryl Hydrocarbon Hydroxylases Vestibule Labyrinth MESH: Vestibular Diseases Nitrile medicine.drug Equilibri (Fisiologia) CYP2A5 Cyanide MESH: Vestibular Function Tests Vestibular toxicity Acetone Productes químics 03 medical and health sciences Ototoxicity MESH: Cyanides Nitriles medicine Animals Toxicologia [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Cytochrome P450 Family 2 Chemical products MESH: Mice 030304 developmental biology Cyanides Dose-Response Relationship Drug Methoxsalen Vertigen Metabolism Vestibular Function Tests medicine.disease Xenobiotic metabolism chemistry Malalties de l'orella MESH: Cytochrome P-450 CYP2E1 Solvents Epoxy Compounds Indicators and Reagents MESH: Vestibule Labyrinth 030217 neurology & neurosurgery Drug metabolism |
| Zdroj: | Review of Economic Dynamics Review of Economic Dynamics, Elsevier, 2009, 107 (2), pp.461-72. ⟨10.1093/toxsci/kfn233⟩ Recercat. Dipósit de la Recerca de Catalunya instname Digital.CSIC. Repositorio Institucional del CSIC Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 1094-2025 1096-0929 |
| Popis: | 12 pages, 9 figures, 1 table.-- PMID: 18990727 [PubMed]. This study addressed the hypothesis that the vestibular or lethal toxicities of allylnitrile depend on CYP2E1-mediated bioactivation. Wild-type (129S1) and CYP2E1-null male mice were exposed to allylnitrile at doses of 0, 0.5, 0.75, or 1.0 mmol/kg (po), following exposure to drinking water with 0 or 1% acetone, which induces CYP2E1 expression. Induction of CYP2E1 activity by acetone in 129S1 mice and lack of activity in null mice was confirmed in liver microsomes. Vestibular toxicity was assessed using a behavioral test battery and illustrated by scanning electron microscopy observation of the sensory epithelia. In parallel groups, concentrations of allylnitrile and cyanide were assessed in blood after exposure to 0.75 mmol/kg of allylnitrile. Following allylnitrile exposure, mortality was lower in CYP2E1-null than in 129S1 mice, and increased after acetone pretreatment only in 129S1 mice. This increase was associated with higher blood concentrations of cyanide. In contrast, no consistent differences were recorded in vestibular toxicity between 129S1 and CYP2E1-null mice, and between animals pretreated with acetone or not. Additional experiments evaluated the effect on the toxicity of 1.0 mmol/kg allylnitrile of the nonselective P450 inhibitor, 1-aminobenzotriazole, the CYP2E1-inhibitor, diallylsulfide, and the CYP2A5 inhibitor, methoxsalen. In 129S1 mice, aminobenzotriazole decreased both mortality and vestibular toxicity, whereas diallylsulfide decreased mortality only. In CYP2E1-null mice, aminobenzotriazole and methoxsalen, but not diallylsulfide, blocked allylnitrile-induced vestibular toxicity. We conclude that CYP2E1-mediated metabolism of allylnitrile leads to cyanide release and acute mortality, probably through alpha-carbon hydroxylation, and hypothesize that epoxidation of the beta-gamma double bond by CYP2A5 mediates vestibular toxicity. Ministry of Science and Innovation (Spain)/Fondo Europeo de Desarrollo Regional (European Union) (grant numbers BFU2006-00343/BFI, CGL2005-02846/BOS); Generalitat of Catalonia (grant number 2005SGR00022); and Centre National d'Etudes Spatiales (France) (grant number DAR2006/2007). |
| Databáze: | OpenAIRE |
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