title: CYP2E1 induction leads to oxidative stress and cytotoxicity in glutathione-depleted cerebellar granule neurons.
abstract: Increasing evidence suggests that brain cytochrome P450 (CYP) can contribute to the in situ metabolism of xenobiotics. In the liver, some xenobiotics can be metabolized by CYPs into more reactive products that can damage hepatocytes and induce cell death. In addition, normal CYP activity may produce reactive oxygen species (ROS) that contribute to cell damage through oxidative mechanisms. CYP2E1 is a CYP isoform that can generate ROS leading to cytotoxicity in multiple tissue types. The aim of this study was to determine whether CYP2E1 induction may lead to significant brain cell impairment. Immunological analysis revealed that exposure of primary cerebellar granule neuronal cultures to the CYP inducer isoniazid, increased CYP2E1 expression. In the presence of buthionine sulfoximine, an agent that reduces glutathione levels, isoniazid treatment also resulted in reactive oxygen species (ROS) production, DNA oxidation and cell death. These effects were attenuated by simultaneous exposure to diallyl sulfide, a CYP2E1 inhibitor, or to a mimetic of superoxide dismutase/catalase, (Euka). These results suggest that in cases of reduced antioxidant levels, the induction of brain CYP2E1 could represent a risk of in situ neuronal damage.
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, D.F., Mexico.
authors.forename: Ana Carolina
authors.initials: AC
authors.lastname: Valencia-Olvera
authors.affiliation: División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, D.F., Mexico.
authors.forename: Julio
authors.initials: J
authors.lastname: Morán
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, D.F., Mexico.
authors.forename: Rafael
authors.initials: R
authors.lastname: Camacho-Carranza
authors.affiliation: Grupo de Neurociencias, Laboratorio de Canabinoides, Departamento de Fisiología, Facultad de Medicina, Universidad Nacional Autónoma de México, DF, Mexico.
authors.forename: Oscar
authors.initials: O
authors.lastname: Prospéro-García
authors.affiliation: Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, D.F., Mexico. Electronic address: jjea@servidor.unam.mx.
authors.forename: Jesús Javier
authors.initials: JJ
authors.lastname: Espinosa-Aguirre
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D065700:Cytochrome P-450 CYP2E1 Inducers / Q000494:pharmacology*; D004247:DNA / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D007538:Isoniazid / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D065700:Cytochrome P-450 CYP2E1 Inducers; D017382:Reactive Oxygen Species; D004247:DNA; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D007538:Isoniazid
keywords: 8-oxo-dG; BSO; Brain cytochrome P450 2E1; Cerebellar granule cells; Isoniazid; Oxidative stress