title: Induction of brain CYP2E1 by chronic ethanol treatment and related oxidative stress in hippocampus, cerebellum, and brainstem.
abstract: Ethanol is one of the most commonly abused substances, and oxidative stress is an important causative factor in ethanol-induced neurotoxicity. Cytochrome P450 2E1 (CYP2E1) is involved in ethanol metabolism in the brain. This study investigates the role of brain CYP2E1 in the susceptibility of certain brain regions to ethanol neurotoxicity. Male Wistar rats were intragastrically treated with ethanol (3.0 g/kg, 30 days). CYP2E1 protein, mRNA expression, and catalytic activity in various brain regions were respectively assessed by immunoblotting, quantitative quantum dot immunohistochemistry, real-time RT-PCR, and LC-MS. The generation of reactive oxygen species (ROS) was analyzed using a laser confocal scanning microscope. The hippocampus, cerebellum, and brainstem were selectively damaged after ethanol treatment, indicated by both lactate dehydrogenase (LDH) activity and histopathological analysis. Ethanol markedly increased the levels of CYP2E1 protein, mRNA expression, and activity in the hippocampus and cerebellum. CYP2E1 protein and activity were significantly increased by ethanol in the brainstem, with no change in mRNA expression. ROS levels induced by ethanol paralleled the enhanced CYP2E1 proteins in the hippocampus, granular layer and white matter of cerebellum as well as brainstem. Brain CYP2E1 activity was positively correlated with the damage to the hippocampus, cerebellum, and brainstem. These results suggest that the selective sensitivity of brain regions to ethanol neurodegeneration may be attributed to the regional and cellular-specific induction of CYP2E1 by ethanol. The inhibition of CYP2E1 levels may attenuate ethanol-induced oxidative stress via ROS generation.
authors.affiliation: Department of Pharmacology, Basic Medical School of Wuhan University, Wuhan 430071, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhong
authors.forename: Guicheng
authors.initials: G
authors.lastname: Dong
authors.forename: Haiguang
authors.initials: H
authors.lastname: Luo
authors.forename: Jie
authors.initials: J
authors.lastname: Cao
authors.forename: Chang
authors.initials: C
authors.lastname: Wang
authors.forename: Jianyuan
authors.initials: J
authors.lastname: Wu
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: Feng
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects* / Q000378:metabolism; D045744:Cell Line, Tumor; D002531:Cerebellum / Q000187:drug effects* / Q000378:metabolism; D002753:Chlorzoxazone / Q000494:pharmacology; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics* / Q000378:metabolism; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D000431:Ethanol / Q000009:adverse effects*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase; D008297:Male; D018613:Microscopy, Confocal; D009447:Neuroblastoma / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015854:Up-Regulation
chemical_list: D065691:Cytochrome P-450 CYP2E1 Inhibitors; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000431:Ethanol; D007770:L-Lactate Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D002753:Chlorzoxazone