title: Binge alcohol promotes hypoxic liver injury through a CYP2E1-HIF-1α-dependent apoptosis pathway in mice and humans.
abstract: Binge drinking, a common pattern of alcohol ingestion, is known to potentiate liver injury caused by chronic alcohol abuse. This study was aimed at investigating the effects of acute binge alcohol on hypoxia-inducible factor-1α (HIF-1α)-mediated liver injury and the roles of alcohol-metabolizing enzymes in alcohol-induced hypoxia and hepatotoxicity. Mice and human specimens assigned to binge or nonbinge groups were analyzed for blood alcohol concentration (BAC), alcohol-metabolizing enzymes, HIF-1α-related protein nitration, and apoptosis. Binge alcohol promoted acute liver injury in mice with elevated levels of ethanol-inducible cytochrome P450 2E1 (CYP2E1) and hypoxia, both of which were colocalized in the centrilobular areas. We observed positive correlations among elevated BAC, CYP2E1, and HIF-1α in mice and humans exposed to binge alcohol. The CYP2E1 protein levels (r = 0.629, p = 0.001) and activity (r = 0.641, p = 0.001) showed a significantly positive correlation with BAC in human livers. HIF-1α levels were also positively correlated with BAC (r = 0.745, p < 0.001) or CYP2E1 activity (r = 0.792, p < 0.001) in humans. Binge alcohol promoted protein nitration and apoptosis with significant correlations observed between inducible nitric oxide synthase and BAC, CYP2E1, or HIF-1α in human specimens. Binge-alcohol-induced HIF-1α activation and subsequent protein nitration or apoptosis seen in wild type were significantly alleviated in the corresponding Cyp2e1-null mice, whereas pretreatment with an HIF-1α inhibitor, PX-478, prevented HIF-1α elevation with a trend of decreased levels of 3-nitrotyrosine and apoptosis, supporting the roles of CYP2E1 and HIF-1α in binge-alcohol-mediated protein nitration and hepatotoxicity. Thus binge alcohol promotes acute liver injury in mice and humans at least partly through a CYP2E1-HIF-1α-dependent apoptosis pathway.
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
authors.forename: Jun-Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Son
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Abdelmegeed
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA.
authors.forename: Atrayee
authors.initials: A
authors.lastname: Banerjee
authors.affiliation: Gastroenterology Service, Veterans Administration Long Beach Healthcare System, Long Beach, CA 90822, USA; Division of Gastroenterology, University of California at Irvine, Irvine, CA 92697, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Morgan
authors.affiliation: Institute of Forensic Medicine, Seoul National University College of Medicine, Seoul, South Korea. Electronic address: yoosh@snu.ac.kr.
authors.forename: Seong-Ho
authors.initials: SH
authors.lastname: Yoo
authors.affiliation: Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892-9410, USA. Electronic address: bj.song@nih.gov.
authors.forename: Byoung-Joon
authors.initials: BJ
authors.lastname: Song
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D063425:Binge Drinking / Q000201:enzymology* / Q000473:pathology; D015687:Cell Hypoxia; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology* / Q000473:pathology; D019392:Cytochrome P-450 CYP2E1 / Q000502:physiology*; D000431:Ethanol / Q000633:toxicity*; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008297:Male; D057507:Mice, 129 Strain; D008875:Middle Aged; D055815:Young Adult
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1
keywords: Alcohol-metabolizing enzymes; Apoptosis; Binge ethanol; CYP2E1; Free radicals; Human liver injury; Hypoxia; Protein nitration