title: Inhibition of cytochrome P4502E1 by chlormethiazole attenuated acute ethanol-induced fatty liver.
abstract: Cytochrome P4502E1 (CYP2E1) has been demonstrated to play crucial roles in chronic ethanol-induced fatty liver, while its role in acute ethanol-induced fatty liver remains unclear. The current study was designed to evaluate the effects of chlormethiazole (CMZ), a specific inhibitor of CYP2E1, on acute ethanol-induced fatty liver, and to explore the mechanisms. Mice were pretreated with single dose of CMZ (50mg/kg body weight) by intraperitoneal injection or equal volume of saline, and then exposed to three doses of ethanol (5g/kg body weight, 25%, w/v) by gavage with 12h intervals. The mice were sacrificed at 4h after the last ethanol dosing. It was found that CMZ significantly attenuated acute ethanol-induced increase of the hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. Acute ethanol-induced increase of the hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels (two biomarkers for oxidative stress) and decrease of glutathione (GSH) level was significantly suppressed by CMZ. CMZ also suppressed ethanol-induced decline of serum adiponectin level, but did not significantly affect the serum tumor necrosis factor-α (TNF-α) and ethanol levels. Furthermore, a significant decline of p62 protein level was observed in CMZ/ethanol group mice liver compared with that of the ethanol group mice. However, acute ethanol-induced increase of peroxisome proliferator-activated receptor α (PPAR-α) protein level was suppressed by CMZ, while the protein levels of sterol regulatory element-binding protein-1c (SREBP-1) and diacylglycerol acyltransferase 2 (DGAT2) were not significantly affected by ethanol or CMZ. Collectively, the results of the current study demonstrated that CMZ could effectively attenuate acute ethanol-induced fatty liver possibly by suppressing oxidative stress and adiponectin decline, and activating autophagy, which suggest that CYP2E1 might also play important roles in acute ethanol-induced fatty liver.
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan City, Shandong Province 250012, China.
authors.forename: Yang-Yang
authors.initials: YY
authors.lastname: Chen
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan City, Shandong Province 250012, China.
authors.forename: Cui-Li
authors.initials: CL
authors.lastname: Zhang
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan City, Shandong Province 250012, China.
authors.forename: Xiu-Lan
authors.initials: XL
authors.lastname: Zhao
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan City, Shandong Province 250012, China.
authors.forename: Ke-Qin
authors.initials: KQ
authors.lastname: Xie
authors.affiliation: Institute of Toxicology, School of Public Health, Shandong University, 44 Wenhua West Road, Jinan City, Shandong Province 250012, China. Electronic address: zengtao@sdu.edu.cn.
authors.forename: Tao
authors.initials: T
authors.lastname: Zeng
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D052242:Adiponectin / Q000097:blood; D000818:Animals; D001343:Autophagy / Q000187:drug effects; D019735:Carbon-Carbon Ligases / Q000378:metabolism; D002719:Chlormethiazole / Q000494:pharmacology*; D065691:Cytochrome P-450 CYP2E1 Inhibitors / Q000494:pharmacology*; D051048:Diacylglycerol O-Acyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D064429:Fatty Acid Synthases / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D065691:Cytochrome P-450 CYP2E1 Inhibitors; D047493:PPAR alpha; D012333:RNA, Messenger; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D002719:Chlormethiazole; C516957:DGAT2 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D064429:Fatty Acid Synthases; D055372:AMP-Activated Protein Kinases; D019735:Carbon-Carbon Ligases; C018757:acyl-CoA carboxylase
keywords: Alcoholic fatty liver; Autophagy; Binge drinking; CYP2E1; Chlormethiazole; Oxidative stress