Binge alcohol promotes hypoxic liver injury through a CYP2E1–HIF-1α-dependent apoptosis pathway in mice and humans

• Published in: Free radical biology & medicine 2014-12, Vol.77, p.183-194
• Main Authors: Yun, Jun-Won, Son, Min-Jeong, Abdelmegeed, Mohamed A., Banerjee, Atrayee, Morgan, Timothy R., Yoo, Seong-Ho, Song, Byoung-Joon
• Format: Article
• Language: English
• Subjects: Adenovirus; Adolescent; Adult; Aged; Alcohol-metabolizing enzymes; Animals; Apoptosis; Binge Drinking - enzymology; Binge Drinking - pathology; Binge ethanol; Cell Hypoxia; Chemical and Drug Induced Liver Injury - enzymology; Chemical and Drug Induced Liver Injury - pathology; CYP2E1; Cytochrome P-450 CYP2E1 - physiology; Ethanol - toxicity; Female; Free radicals; Human liver injury; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Liver - enzymology; Liver - pathology; Male; Mice, 129 Strain; Middle Aged; Protein nitration; Young Adult
• ISSN: 0891-5849; 1873-4596
• DOI: 10.1016/j.freeradbiomed.2014.08.030

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. [Display omitted] •Hepatic CYP2E1 was related to hypoxia and HIF-1α induction after binge alcohol.•Binge alcohol promoted HIF-1α-related apoptosis and protein nitration.•Effects of binge alcohol in humans were replicated in a mouse model of binge-alcohol-induced liver injury.•CYP2E1 and HIF-1α can be valuable targets to treat alcohol-induced liver injury.