title: The induction of cytochrome P450 2E1 by ethanol leads to the loss of synaptic proteins via PPARα down-regulation.
abstract: Ethanol, one of the most commonly abused substances throughout history, is a substrate and potent inducer of cytochrome P450 2E1 (CYP2E1). Our previous study showed that brain CYP2E1 was induced by chronic ethanol treatment and was associated with ethanol-induced neurotoxicity in rats. We therefore investigated the possible mechanism of brain CYP2E1 involvement in ethanol-induced neurodegeneration. Compared with the controls, chronic ethanol treatment (3.0g/kg, i.g., 160days) significantly increased CYP2E1 mRNA levels in the rat cortex, but the mRNA levels of peroxisome proliferator-activated receptor α (PPARα) and the pre- and post-synaptic proteins (synaptophysin, SYP, and drebrin1, DBN1) were decreased. Ethanol treatment dose-dependently induced CYP2E1 mRNA expression, and CYP2E1 overexpression exacerbated the ethanol-induced neurotoxicity. Pretreatment with p38 inhibitor (SB202190) and ERK1/2 inhibitor (U0126) attenuated the induction of CYP2E1 mRNA and protein levels by ethanol; however, no change was observed with JNK inhibitor pretreatment. Ethanol exposure or CYP2E1 overexpression significantly decreased PPARα, SYP, and DBN1 expression as indicated by the data from real-time RT-PCR, Western blotting and immunocytochemistry. The activation of PPARα by WY14643 increased the activity of the SYP and DBN1 promoters and attenuated the inhibition of these genes by ethanol. The specific siRNA for CYP2E1 significantly attenuated the ethanol-induced inhibition of PPARα, SYP and DBN1 mRNA levels. These results suggest that the induction of CYP2E1 by ethanol may be mediated via the p38 and ERK1/2 signaling pathways in neurons but not via the JNK pathway. The CYP2E1-PPARα axis may play a role in ethanol-induced neurotoxicity via the alteration of the genes related with synaptic function.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Shufang
authors.initials: S
authors.lastname: Na
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Yueran
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Zheqiong
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Yanjun
authors.initials: Y
authors.lastname: Zhong
authors.affiliation: Baotou Teachers' College, Inner Mongolia University of Science & Technology, Baotou 014030, China.
authors.forename: Guicheng
authors.initials: G
authors.lastname: Dong
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Hubei Province Key Laboratory of Allergy and Immunology, Wuhan 430060, China. Electronic address: yuejiang@whu.edu.cn.
authors.forename: Jiang
authors.initials: J
authors.lastname: Yue
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004790:Enzyme Induction / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics*; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D017208:Rats, Wistar; D013569:Synapses / Q000378:metabolism; D016708:Synaptophysin / Q000235:genetics*
chemical_list: D009479:Neuropeptides; D047493:PPAR alpha; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016708:Synaptophysin; C569016:Syp protein, rat; C053386:drebrins; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D020928:Mitogen-Activated Protein Kinases
keywords: Cytochrome P450 2E1; Drebrin1; Ethanol; PPARα; Synaptophysin