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CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis.
Free Radic Biol Med. 2013 Dec; 65:1238-1245.FR

Abstract

Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis.

Authors+Show Affiliations

Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.Department of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea.Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.Division of Gastroenterology, Rush University Medical Center, Chicago, IL 60612, USA.Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA. Electronic address: bj.song@nih.gov.

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural

Language

eng

PubMed ID

24064383

Citation

Abdelmegeed, Mohamed A., et al. "CYP2E1 Potentiates Binge Alcohol-induced Gut Leakiness, Steatohepatitis, and Apoptosis." Free Radical Biology & Medicine, vol. 65, 2013, pp. 1238-1245.
Abdelmegeed MA, Banerjee A, Jang S, et al. CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radic Biol Med. 2013;65:1238-1245.
Abdelmegeed, M. A., Banerjee, A., Jang, S., Yoo, S. H., Yun, J. W., Gonzalez, F. J., Keshavarzian, A., & Song, B. J. (2013). CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. Free Radical Biology & Medicine, 65, 1238-1245. https://doi.org/10.1016/j.freeradbiomed.2013.09.009
Abdelmegeed MA, et al. CYP2E1 Potentiates Binge Alcohol-induced Gut Leakiness, Steatohepatitis, and Apoptosis. Free Radic Biol Med. 2013;65:1238-1245. PubMed PMID: 24064383.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - CYP2E1 potentiates binge alcohol-induced gut leakiness, steatohepatitis, and apoptosis. AU - Abdelmegeed,Mohamed A, AU - Banerjee,Atrayee, AU - Jang,Sehwan, AU - Yoo,Seong-Ho, AU - Yun,Jun-Won, AU - Gonzalez,Frank J, AU - Keshavarzian,Ali, AU - Song,Byoung-Joon, Y1 - 2013/09/21/ PY - 2013/08/05/received PY - 2013/09/12/revised PY - 2013/09/17/accepted PY - 2013/9/26/entrez PY - 2013/9/26/pubmed PY - 2014/9/3/medline KW - 3-NT KW - 3-nitrotyrosine KW - AFLD KW - ALD KW - ALDH2 KW - ALT KW - ASH KW - Apoptosis KW - Binge ethanol KW - CMZ KW - CYP2E1 KW - Cyp2e1-null–dextrose KW - Cyp2e1-null–ethanol KW - Free radicals KW - Gut leakiness KW - HAE KW - HPF KW - Liver KW - MDA KW - N-acetylcysteine KW - NAC KW - NAFLD KW - NASH KW - Oxidative stress KW - PPAR-α KW - RNS KW - ROS KW - SOD2 KW - Steatohepatitis KW - TG KW - TNF-α KW - TUNEL KW - WT KW - WT-DEX KW - WT-EtOH KW - alanine aminotransferase KW - alcoholic fatty liver disease KW - alcoholic liver disease KW - alcoholic steatohepatitis KW - chlormethiazole KW - cytochrome P450 2E1 KW - high-power field KW - hydroxyalkenal KW - malondialdehyde KW - mitochondrial aldehyde dehydrogenase 2 KW - mitochondrial superoxide dismutase KW - nonalcoholic fatty liver disease KW - nonalcoholic steatohepatitis KW - null–DEX KW - null–EtOH KW - peroxisome proliferator-activated receptor-α KW - reactive nitrogen species KW - reactive oxygen species KW - terminal deoxynucleotidyl transferase dUTP nick-end labeling KW - triglyceride KW - tumor necrosis factor-α KW - wild-type KW - wild-type–dextrose KW - wild-type–ethanol. SP - 1238 EP - 1245 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 65 N2 - Ethanol-inducible cytochrome P450 2E1 (CYP2E1) contributes to increased oxidative stress and steatosis in chronic alcohol-exposure models. However, its role in binge ethanol-induced gut leakiness and hepatic injury is unclear. This study was aimed at investigating the role of CYP2E1 in binge alcohol-induced gut leakiness and the mechanisms of steatohepatitis. Female wild-type (WT) and Cyp2e1-null mice were treated with three doses of binge ethanol (WT-EtOH or Cyp2e1-null-EtOH) (6g/kg oral gavage at 12-h intervals) or dextrose (negative control). Intestinal histology of only WT-EtOH exhibited epithelial alteration and blebbing of lamina propria, and liver histology obtained at 6h after the last ethanol dose showed elevated steatosis with scattered inflammatory foci. These were accompanied by increased levels of serum endotoxin, hepatic enterobacteria, and triglycerides. All these changes, including the intestinal histology and hepatic apoptosis, determined by TUNEL assay, were significantly reversed when WT-EtOH mice were treated with the specific inhibitor of CYP2E1 chlormethiazole and the antioxidant N-acetylcysteine, both of which suppressed oxidative markers including intestinal CYP2E1. WT-EtOH also exhibited elevated amounts of serum TNF-α, hepatic cytokines, CYP2E1, and lipid peroxidation, with decreased levels of mitochondrial superoxide dismutase and suppressed aldehyde dehydrogenase 2 activity. Increased hepatocyte apoptosis with elevated levels of proapoptotic proteins and decreased levels of active (phosphorylated) p-AKT, p-AMPK, and peroxisome proliferator-activated receptor-α, all of which are involved in fat metabolism and inflammation, were observed in WT-EtOH. These changes were significantly attenuated in the corresponding Cyp2e1-null-EtOH mice. These data indicate that both intestinal and hepatic CYP2E1 induced by binge alcohol seems critical in binge alcohol-mediated increased nitroxidative stress, gut leakage, and endotoxemia; altered fat metabolism; and inflammation contributing to hepatic apoptosis and steatohepatitis. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/24064383/CYP2E1_potentiates_binge_alcohol_induced_gut_leakiness_steatohepatitis_and_apoptosis_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(13)00612-6 DB - PRIME DP - Unbound Medicine ER -