Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study.

Biewald, J; Nilius, R; Langner, Jürgen

doi:10.3892/ijmm.2.4.389

Cited by 7 publications

(6 citation statements)

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“…Acetaldehyde impairs cellular functions and gene expression by forming adducts with proteins and DNA 11,16,38,39. Acetaldehyde produces protein adducts by interacting with the epsilon amino group of lysine, or the α amino group of N-terminal amino acids 12.…”

Section: Acetaldehyde As An Indirect Carcinogenmentioning

confidence: 99%

Acetaldehyde Adducts in Alcoholic Liver Disease

Setshedi

Wands

Monte

2010

Oxidative Medicine and Cellular Longevity

288

204

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Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD), with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC). Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2–15%) versus cirrhosis (15–20%) is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.

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Section: Acetaldehyde As An Indirect Carcinogenmentioning

confidence: 99%

Acetaldehyde Adducts in Alcoholic Liver Disease

Setshedi

Wands

Monte

2010

Oxidative Medicine and Cellular Longevity

288

204

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“…As a result of its electrophilic nature, acetaldehyde [8] can bind and form covalent chemical adducts with proteins, lipids and DNA [9][10][11][12][13] . These adducts are broadly pathogenic because they alter cell homeostasis, changing protein structure [11,12,14,15] and promoting DNA damage and mutation.…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Ceni

Mello

Galli

2014

WJG

413

339

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Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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“…Acetaldehyde, a metabolic product of ethanol, is highly toxic to cells owing to formation of adducts with DNA (5) and proteins (4,22,40), leading to epigenetic and posttranslational consequences in different cells (13,43). Acetaldehyde is produced in the colonic lumen as a result of normal bacterial fermentation, which is elevated dramatically following alcohol consumption.…”

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confidence: 99%

Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism

Dunagan

Chaudhry

Samak

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Acetaldehyde is accumulated at high concentrations in the colonic lumen following ethanol administration. Previous studies demonstrated that acetaldehyde disrupts intestinal epithelial tight junctions and increases paracellular permeability. In the present study, we investigated the role of PP2A in the acetaldehyde-induced disruption of intestinal epithelial tight junctions. Caco-2 cell monolayers were exposed to 200-600 μM acetaldehyde for varying times, and the epithelial barrier function was evaluated by measuring transepithelial electrical resistance and inulin permeability. Acetaldehyde treatment resulted in a time-dependent increase in inulin permeability and redistribution of occludin and ZO-1 from the intercellular junctions. Treatment of cells with fostriecin (a PP2A-selective inhibitor) or knockdown of PP2A by siRNA blocked acetaldehyde-induced increase in inulin permeability and redistribution of occludin and ZO-1. The effects of fostriecin and acetaldehyde were confirmed in mouse intestine ex vivo. Acetaldehyde-induced tight junction disruption and barrier dysfunction were also attenuated by a PP2A-specific inhibitory peptide, TPDYFL. Coimmunoprecipitation studies showed that acetaldehyde increased the interaction of PP2A with occludin and induced dephosphorylation of occludin on threonine residues. Fostriecin and TPDYFL significantly reduced acetaldehyde-induced threonine dephosphorylation of occludin. Acetaldehyde failed to change the level of the methylated form of PP2A-C subunit. However, genistein (a tyrosine kinase inhibitor) blocked acetaldehyde-induced association of PP2A with occludin and threonine dephosphorylation of occludin. These results demonstrate that acetaldehyde-induced disruption of tight junctions is mediated by PP2A translocation to tight junctions and dephosphorylation of occludin on threonine residues.

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Occurrence of acetaldehyde protein adducts formed in various organs of chronically ethanol fed rats: an immunohistochemical study.

Cited by 7 publications

References 0 publications

Acetaldehyde Adducts in Alcoholic Liver Disease

Acetaldehyde Adducts in Alcoholic Liver Disease

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

Acetaldehyde disrupts tight junctions in Caco-2 cell monolayers by a protein phosphatase 2A-dependent mechanism

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