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Nutrients Sep 2021Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper... (Review)
Review
Approximately 4% of cancers worldwide are caused by alcohol consumption. Drinking alcohol increases the risk of several cancer types, including cancers of the upper aerodigestive tract, liver, colorectum, and breast. In this review, we summarise the epidemiological evidence on alcohol and cancer risk and the mechanistic evidence of alcohol-mediated carcinogenesis. There are several mechanistic pathways by which the consumption of alcohol, as ethanol, is known to cause cancer, though some are still not fully understood. Ethanol's metabolite acetaldehyde can cause DNA damage and block DNA synthesis and repair, whilst both ethanol and acetaldehyde can disrupt DNA methylation. Ethanol can also induce inflammation and oxidative stress leading to lipid peroxidation and further DNA damage. One-carbon metabolism and folate levels are also impaired by ethanol. Other known mechanisms are discussed. Further understanding of the carcinogenic properties of alcohol and its metabolites will inform future research, but there is already a need for comprehensive alcohol control and cancer prevention strategies to reduce the burden of cancer attributable to alcohol.
Topics: Acetaldehyde; Alcohol Drinking; Alcohol-Induced Disorders; Carcinogenesis; DNA Damage; DNA Methylation; Ethanol; Humans; Neoplasms
PubMed: 34579050
DOI: 10.3390/nu13093173 -
International Journal of Biological... 2020Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver. In addition to conversion of the... (Review)
Review
Acetaldehyde dehydrogenase 2 (ALDH2) is the key enzyme responsible for metabolism of the alcohol metabolite acetaldehyde in the liver. In addition to conversion of the acetaldehyde molecule, ALDH is also involved in other cellular functions. Recently, many studies have investigated the involvement of ALDH expression in viral hepatitis, alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), liver fibrosis, and liver cancer. Notably, ALDH2 expression has been linked with liver cancer risk, as well as pathogenesis and prognosis, and has emerged as a promising therapeutic target. Of note, approximately 8% of the world's population, and approximately 30-40% of the population in East Asia carry an inactive gene. This review summarizes new progress in understanding tissue-specific acetaldehyde metabolism by ALDH2 as well as the association of gene polymorphisms with liver disease and cancer. New research directions emerging in the field are also briefly discussed.
Topics: Aldehyde Dehydrogenase; Animals; Humans; Liver; Liver Neoplasms; Polymorphism, Genetic
PubMed: 32140062
DOI: 10.7150/ijbs.42300 -
World Journal of Gastroenterology Dec 2014Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis,... (Review)
Review
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.
Topics: Acetaldehyde; Adaptive Immunity; Animals; Disease Progression; Ethanol; Humans; Immunity, Innate; Liver; Liver Diseases, Alcoholic; Oxidation-Reduction; Oxidative Stress; Prognosis; Reactive Oxygen Species; Risk Factors; Signal Transduction
PubMed: 25548474
DOI: 10.3748/wjg.v20.i47.17756 -
Revue Medicale de Liege May 2019Ethanol is rapidly and almost completely absorbed by the digestive tract, mainly in the small intestine. Alcohol is then metabolized mainly in the liver where it is...
Ethanol is rapidly and almost completely absorbed by the digestive tract, mainly in the small intestine. Alcohol is then metabolized mainly in the liver where it is converted into acetaldehyde. Two systems contribute to this metabolization, the predominant alcohol dehydrogenase pathway, and the pathway controlled by the microsomal ethanol oxidizing system (MEOS), which is inducible and is also involved in the metabolism of other drugs. Acetaldehyde is then metabolized to acetate, which largely leaves the liver to be converted into acetyl-CoA in other tissues. Alcohol is oxidized preferentially to other energetic substrates, leading, in turn, to a decrease in oxidation of lipids which are stored in adipose tissue.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Ethanol; Humans; Liver; Oxidation-Reduction
PubMed: 31206264
DOI: No ID Found -
Autophagy Nov 2022Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In...
Ethanol increases hepatic mitophagy driven by unknown mechanisms. Type 1 mitophagy sequesters polarized mitochondria for nutrient recovery and cytoplasmic remodeling. In Type 2, mitochondrial depolarization (mtDepo) initiates mitophagy to remove the damaged organelles. Previously, we showed that acute ethanol administration produces reversible hepatic mtDepo. Here, we tested the hypothesis that ethanol-induced mtDepo initiates Type 2 mitophagy. GFP-LC3 transgenic mice were gavaged with ethanol (2-6 g/kg) with and without pre-treatment with agents that decrease or increase mtDepo-Alda-1, tacrolimus, or disulfiram. Without ethanol, virtually all hepatocytes contained polarized mitochondria with infrequent autophagic GFP-LC3 puncta visualized by intravital microscopy. At ~4 h after ethanol treatment, mtDepo occurred in an all-or-none fashion within individual hepatocytes, which increased dose dependently. GFP-LC3 puncta increased in parallel, predominantly in hepatocytes with mtDepo. Mitochondrial PINK1 and PRKN/parkin also increased. After covalent labeling of mitochondria with MitoTracker Red (MTR), GFP-LC3 puncta encircled MTR-labeled mitochondria after ethanol treatment, directly demonstrating mitophagy. GFP-LC3 puncta did not associate with fat droplets visualized with BODIPY558/568, indicating that increased autophagy was not due to lipophagy. Before ethanol administration, rhodamine-dextran (RhDex)-labeled lysosomes showed little association with GFP-LC3. After ethanol treatment, TFEB (transcription factor EB) translocated to nuclei, and lysosomal mass increased. Many GFP-LC3 puncta merged with RhDex-labeled lysosomes, showing autophagosomal processing into lysosomes. After ethanol treatment, disulfiram increased, whereas Alda-1 and tacrolimus decreased mtDepo, and mitophagy changed proportionately. In conclusion, mtDepo after acute ethanol treatment induces mitophagic sequestration and subsequent lysosomal processing. AcAld, acetaldehyde; ADH, alcohol dehydrogenase; ALDH, aldehyde dehydrogenase; ALD, alcoholic liver disease; Alda-1, N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LMNB1, lamin B1; MAA, malondialdehyde-acetaldehyde adducts; MAP1LC3/LC3, microtubule-associated protein 1 light chain 3; MPT, mitochondrial permeability transition; mtDAMPS, mitochondrial damage-associated molecular patterns; mtDepo, mitochondrial depolarization; mtDNA, mitochondrial DNA; MTR, MitoTracker Red; PI, propidium iodide; PINK1, PTEN induced putative kinase 1; PRKN, parkin; RhDex, rhodamine dextran; TFEB, transcription factor EB; Tg, transgenic; TMRM, tetramethylrhodamine methylester; TOMM20, translocase of outer mitochondrial membrane 20; VDAC, voltage-dependent anion channel.
Topics: Mice; Animals; Mitophagy; Ethanol; Disulfiram; Tacrolimus; Autophagy; Ubiquitin-Protein Ligases; DNA, Mitochondrial; Protein Kinases; Acetaldehyde
PubMed: 35293288
DOI: 10.1080/15548627.2022.2046457 -
International Journal of Environmental... Dec 2021Alcohol abuse disorder is a serious condition, implicating more than 15 million people aged 12 years and older in 2019 in the United States. Ethanol (or ethyl alcohol)... (Review)
Review
Alcohol abuse disorder is a serious condition, implicating more than 15 million people aged 12 years and older in 2019 in the United States. Ethanol (or ethyl alcohol) is mainly oxidized in the liver, resulting in the synthesis of acetaldehyde and acetate, which are toxic and carcinogenic metabolites, as well as in the generation of a reductive cellular environment. Moreover, ethanol can interact with lipids, generating fatty acid ethyl esters and phosphatidylethanol, which interfere with physiological cellular pathways. This narrative review summarizes the impact of excessive alcohol consumption on male fertility by describing its metabolism and how ethanol consumption may induce cellular damage. Furthermore, the impact of alcohol consumption on hormonal regulation, semen quality, and genetic and epigenetic regulations is discussed based on evidence from animal and human studies, focusing on the consequences on the offspring. Finally, the limitations of the current evidence are discussed. Our review highlights the association between chronic alcohol consumption and poor semen quality, mainly due to the development of oxidative stress, as well as its genotoxic impact on hormonal regulation and DNA integrity, affecting the offspring's health. New landscapes of investigation are proposed for the identification of molecular markers for alcohol-associated infertility, with a focus on advanced OMICS-based approaches applied to the analysis of semen samples.
Topics: Acetaldehyde; Alcohol Drinking; Animals; Ethanol; Fertility; Humans; Male; Semen Analysis
PubMed: 35010587
DOI: 10.3390/ijerph19010328 -
Frontiers in Behavioral Neuroscience 2017After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths.... (Review)
Review
After decades of uncertainties and drawbacks, the study on the role and significance of acetaldehyde in the effects of ethanol seemed to have found its main paths. Accordingly, the effects of acetaldehyde, after its systemic or central administration and as obtained following ethanol metabolism, looked as they were extensively characterized. However, almost 5 years after this research appeared at its highest momentum, the investigations on this topic have been revitalized on at least three main directions: (1) the role and the behavioral significance of acetaldehyde in different phases of ethanol self-administration and in voluntary ethanol consumption; (2) the distinction, in the central effects of ethanol, between those arising from its non-metabolized fraction and those attributable to ethanol-derived acetaldehyde; and (3) the role of the acetaldehyde-dopamine condensation product, salsolinol. The present review article aims at presenting and discussing prospectively the most recent data accumulated following these three research pathways on this never-ending story in order to offer the most up-to-date synoptic critical view on such still unresolved and exciting topic.
PubMed: 28553209
DOI: 10.3389/fnbeh.2017.00081 -
Advances in Experimental Medicine and... 2015Colorectal cancer (CRC) and pancreatic cancer are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for... (Review)
Review
Colorectal cancer (CRC) and pancreatic cancer are two very significant contributors to cancer-related deaths. Chronic alcohol consumption is an important risk factor for these cancers. Ethanol is oxidized primarily by alcohol dehydrogenases to acetaldehyde, an agent capable of initiating tumors by forming adducts with proteins and DNA. Acetaldehyde is metabolized by ALDH2, ALDH1B1, and ALDH1A1 to acetate. Retinoic acid (RA) is required for cellular differentiation and is known to arrest tumor development. RA is synthesized from retinaldehyde by the retinaldehyde dehydrogenases, specifically ALDH1A1, ALDH1A2, ALDH1A3, and ALDH8A1. By eliminating acetaldehyde and generating RA, ALDHs can play a crucial regulatory role in the initiation and progression of cancers. ALDH1 catalytic activity has been used as a biomarker to identify and isolate normal and cancer stem cells; its presence in a tumor is associated with poor prognosis in colon and pancreatic cancer. In summary, these ALDHs are not only biomarkers for CRC and pancreatic cancer but also play important mechanistic role in cancer initiation, progression, and eventual prognosis.
Topics: Acetaldehyde; Aldehyde Dehydrogenase; Cell Proliferation; Colorectal Neoplasms; Humans; Pancreatic Neoplasms; Retinaldehyde; Tretinoin
PubMed: 25427913
DOI: 10.1007/978-3-319-09614-8_16 -
Cellular and Molecular Gastroenterology... 2023Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We...
BACKGROUND & AIMS
Binge drinking in patients with metabolic syndrome accelerates the development of alcohol-associated liver disease. However, the underlying mechanisms remain elusive. We investigated if oxidative and nonoxidative alcohol metabolism pathways, diet-induced obesity, and adipose tissues influenced the development of acute liver injury in a single ethanol binge model.
METHODS
A single ethanol binge was administered to chow-fed or high-fat diet (HFD)-fed wild-type and genetically modified mice.
RESULTS
Oral administration of a single dose of ethanol induced acute liver injury and hepatic endoplasmic reticulum (ER) stress in chow- or HFD-fed mice. Disruption of the Adh1 gene increased blood ethanol concentration and exacerbated acute ethanol-induced ER stress and liver injury in both chow-fed and HFD-fed mice, while disruption of the Aldh2 gene did not affect such hepatic injury despite high blood acetaldehyde levels. Mechanistic studies showed that alcohol, not acetaldehyde, promoted hepatic ER stress, fatty acid synthesis, and increased adipocyte death and lipolysis, contributing to acute liver injury. Increased serum fatty acid ethyl esters (FAEEs), which are formed by an enzyme-mediated esterification of ethanol with fatty acids, were detected in mice after ethanol gavage, with higher levels in Adh1 knockout mice than in wild-type mice. Deletion of the Ces1d gene in mice markedly reduced the acute ethanol-induced increase of blood FAEE levels with a slight but significant reduction of serum aminotransferase levels.
CONCLUSIONS
Ethanol and its nonoxidative metabolites, FAEEs, not acetaldehyde, promoted acute alcohol-induced liver injury by inducing ER stress, adipocyte death, and lipolysis.
Topics: Animals; Mice; Acetaldehyde; Adipocytes; Esters; Ethanol; Fatty Acids; Lipolysis; Liver; Endoplasmic Reticulum Stress; Chemical and Drug Induced Liver Injury
PubMed: 36243320
DOI: 10.1016/j.jcmgh.2022.10.002 -
Applied Microbiology and Biotechnology Dec 20182-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective... (Review)
Review
2-Deoxy-D-ribose-5-phosphate aldolase (DERA) is a class I aldolase that offers access to several building blocks for organic synthesis. It catalyzes the stereoselective C-C bond formation between acetaldehyde and numerous other aldehydes. However, the practical application of DERA as a biocatalyst is limited by its poor tolerance towards industrially relevant concentrations of aldehydes, in particular acetaldehyde. Therefore, the development of proper experimental conditions, including protein engineering and/or immobilization on appropriate supports, is required. The present review is aimed to provide a brief overview of DERA, its history, and progress made in understanding the functioning of the enzyme. Furthermore, the current understanding regarding aldehyde resistance of DERA and the various optimizations carried out to modify this property are discussed.
Topics: Acetaldehyde; Aldehyde-Lyases; Aldehydes; Catalysis; Protein Conformation; Protein Engineering; Ribosemonophosphates; Substrate Specificity
PubMed: 30284013
DOI: 10.1007/s00253-018-9392-8