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Current Topics in Behavioral... 2013Alcohol abuse and alcoholism represent substantial problems that affect a large portion of individuals throughout the world. Extensive research continues to be conducted... (Review)
Review
Alcohol abuse and alcoholism represent substantial problems that affect a large portion of individuals throughout the world. Extensive research continues to be conducted in an effort to identify the biological basis of the reinforcing properties of alcohol in order to develop effective pharmacotherapeutic and behavioral interventions. One theory that has developed within the alcohol field over the past four decades postulates that the reinforcing properties of alcohol are due to the action of the metabolites/products of alcohol within the central nervous system (CNS). The most extreme version of this theory suggests that the biologically active metabolites/products of alcohol, created from the breakdown from alcohol, are the ultimate source of the reinforcing properties of alcohol. The contrary theory proposes that the reinforcing properties of alcohol are mediated completely through the interaction of the ethanol molecule with several neurochemical systems within the CNS. While there are scientific findings that offer support for both of these stances, the reinforcing properties of alcohol are most likely generated through a complex series of peripheral and central effects of both alcohol and its metabolites. Nonetheless, the development of a greater understanding for how the metabolites/products of alcohol contribute to the reinforcing properties of alcohol is an important factor in the development of efficacious pharmacotherapies for alcohol abuse and alcoholism. This chapter is intended to provide a historical perspective of the role of acetaldehyde (the first metabolite of alcohol) in alcohol reinforcement as well as review the basic research literature on the effects of acetaldehyde (and acetaldehyde metabolites/products) within the CNS and how these function with regard to alcohol reward.
Topics: Acetaldehyde; Alcohol Drinking; Alcoholism; Animals; Central Nervous System; Ethanol; Humans; Isoquinolines
PubMed: 22351424
DOI: 10.1007/7854_2011_198 -
Alcohol-induced tubulin post-translational modifications directly alter hepatic protein trafficking.Hepatology Communications Apr 2023Chronic ethanol exposure leads to enhanced protein acetylation and acetaldehyde adduction. Of the multitude of proteins that are modified on ethanol administration,...
BACKGROUND
Chronic ethanol exposure leads to enhanced protein acetylation and acetaldehyde adduction. Of the multitude of proteins that are modified on ethanol administration, tubulin is among the best studied. However, an open question is whether these modifications are observed in patient samples. Both modifications have also been implicated in promoting alcohol-induced defects in protein trafficking, but whether they do so directly is also unanswered.
METHODS AND RESULTS
We first confirmed that tubulin was hyperacetylated and acetaldehyde-adducted in the livers from ethanol-exposed individuals to a similar extent as observed in the livers from ethanol-fed animals and hepatic cells. Livers from individuals with nonalcohol-associated fatty liver showed modest increases in tubulin acetylation, whereas nonalcohol-associated fibrotic human and mouse livers showed virtually no tubulin modifications. We also asked whether tubulin acetylation or acetaldehyde adduction can directly explain the known alcohol-induced defects in protein trafficking. Acetylation was induced by overexpressing the α-tubulin-specific acetyltransferase, αTAT1, whereas adduction was induced by directly adding acetaldehyde to cells. Both αTAT1 overexpression and acetaldehyde treatment significantly impaired plus-end (secretion) and minus-end (transcytosis)-directed microtubule-dependent trafficking and clathrin-mediated endocytosis. Each modification led to similar levels of impairment as observed in ethanol-treated cells. The levels of impairment by either modification showed no dose dependence or no additive effects suggesting that substoichiometric tubulin modifications lead to altered protein trafficking and that lysines are not selectively modified.
CONCLUSIONS
These results not only confirm that enhanced tubulin acetylation is observed in human livers but that it is most relevant to alcohol-induced injury. Because these tubulin modifications are associated with altered protein trafficking that alters proper hepatic function, we propose that changing the cellular acetylation levels or scavenging free aldehydes are feasible strategies for treating alcohol-associated liver disease.
Topics: Mice; Animals; Humans; Tubulin; Ethanol; Liver Diseases, Alcoholic; Acetaldehyde; Protein Processing, Post-Translational; Protein Transport
PubMed: 36972397
DOI: 10.1097/HC9.0000000000000103 -
Biosensors Nov 2022A new spectroelectrochemical two-enzyme sensor system has been developed for the detection of acetaldehyde in wine. A combination of spectroscopy and electrochemistry...
A new spectroelectrochemical two-enzyme sensor system has been developed for the detection of acetaldehyde in wine. A combination of spectroscopy and electrochemistry improves the analytical features of the electrochemical sensor because the optical information collected with this system is only associated with acetaldehyde and avoids the interferents also present in wines as polyphenols. Spectroelectrochemical detection is achieved by the analysis of the optical properties of the K[Fe(CN)]/K[Fe(CN)] redox couple involved in the enzymatic process: aldehyde dehydrogenase catalyzes the aldehyde oxidation using β-nicotinamide adenine dinucleotide hydrate (NAD) as a cofactor and, simultaneously, diaphorase reoxidizes the NADH formed in the first enzymatic process due to the presence of K[Fe(CN)]. An analysis of the characteristic UV-vis bands of K[Fe(CN)] at 310 and 420 nm allows the detection of acetaldehyde, since absorption bands are only related to the oxidation of this substrate, and avoids the contribution of other interferents.
Topics: Acetaldehyde; Wine; NAD; Electrochemistry; Oxidation-Reduction
PubMed: 36421150
DOI: 10.3390/bios12111032 -
Scientific Reports Jun 2022Acetaldehyde, a metabolic product of ethanol, induces DNA damage and genome instability. Accumulation of acetaldehyde due to alcohol consumption or aldehyde...
Acetaldehyde, a metabolic product of ethanol, induces DNA damage and genome instability. Accumulation of acetaldehyde due to alcohol consumption or aldehyde dehydrogenase (ALDH2) deficiency increases the risks of various types of cancers, including esophageal cancer. Although acetaldehyde chemically induces DNA adducts, the repair process of the lesions remains unclear. To investigate the mechanism of repair of acetaldehyde-induced DNA damage, we determined the repair pathway using siRNA knockdown and immunofluorescence assays of repair factors. Herein, we report that acetaldehyde induces DNA double-strand breaks (DSBs) in human U2OS cells and that both DSB repair pathways, non-homologous end-joining (NHEJ) and homology-directed repair (HDR), are required for the repair of acetaldehyde-induced DNA damage. Our findings suggest that acetaldehyde-induced DNA adducts are converted into DSBs and repaired via NHEJ or HDR in human cells. To reduce the risk of acetaldehyde-associated carcinogenesis, we investigated potential strategies of reducing acetaldehyde-induced DNA damage. We report that polyphenols extracted from persimmon fruits and epigallocatechin, a major component of persimmon polyphenols, attenuate acetaldehyde-induced DNA damage without affecting the repair kinetics. The data suggest that persimmon polyphenols suppress DSB formation by scavenging acetaldehyde. Persimmon polyphenols can potentially inhibit carcinogenesis following alcohol consumption.
Topics: Acetaldehyde; Aldehyde Dehydrogenase, Mitochondrial; Carcinogenesis; DNA Adducts; DNA Breaks, Double-Stranded; DNA End-Joining Repair; DNA Repair; Diospyros; Fruit; Humans; Polyphenols
PubMed: 35717470
DOI: 10.1038/s41598-022-14374-9 -
Acta Crystallographica. Section F,... Jun 2023Aldehyde dehydrogenase (ALDH) is widely distributed in nature and its characteristics have been examined. ALDH plays an important role in aldehyde detoxification....
Aldehyde dehydrogenase (ALDH) is widely distributed in nature and its characteristics have been examined. ALDH plays an important role in aldehyde detoxification. Sources of aldehydes include incomplete combustion and emissions from paints, linoleum and varnishes in the living environment. Acetaldehyde is also considered to be carcinogenic and toxic. Thermostable ALDH from the hyperthermophilic archaeon Sulfolobus tokodaii exhibits high activity towards acetaldehyde and has potential applications as a biosensor for acetaldehyde. Thermostable ALDH displays a unique and wide adaptability. Therefore, its crystal structure can provide new insights into the catalytic mechanism and potential applications of ALDHs. However, a crystal structure of a thermostable ALDH exhibiting high activity towards acetaldehyde has not been reported to date. In this study, crystals of recombinant thermostable ALDH from S. tokodaii were prepared and the crystal structure of its holo form was determined. A crystal of the enzyme was prepared and its structure in complex with NADP was determined at a resolution of 2.2 Å. This structural analysis may facilitate further studies on catalytic mechanisms and applications.
Topics: Sulfolobus; Archaea; Crystallography, X-Ray; Acetaldehyde
PubMed: 37227376
DOI: 10.1107/S2053230X23004430 -
Nutrients Apr 2021Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances... (Review)
Review
Benefits and harms of different components of human diet have been known for hundreds of years. Alcohol is one the highest consumed, abused, and addictive substances worldwide. Consequences of alcohol abuse are increased risks for diseases of the cardiovascular system, liver, and nervous system, as well as reduced immune system function. Paradoxically, alcohol has also been a consistent protective factor against the development of autoimmune diseases such as type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis (RA). Here, we focused on summarizing current findings on the effects of alcohol, as well as of its metabolites, acetaldehyde and acetate, on the immune system and RA. Heavy or moderate alcohol consumption can affect intestinal barrier integrity, as well as the microbiome, possibly contributing to RA. Additionally, systemic increase in acetate negatively affects humoral immune response, diminishing T cell as well as professional antigen-presenting cell (APC) function. Hence, alcohol consumption has profound effects on the efficacy of vaccinations, but also elicits protection against autoimmune diseases. The mechanism of alcohol's negative effects on the immune system is multivariate. Future studies addressing alcohol and its metabolite acetate's effect on individual components of the immune system remains crucial for our understanding and development of novel therapeutic pathways.
Topics: Acetaldehyde; Acetates; Alcohol Drinking; Arthritis, Rheumatoid; Ethanol; Humans; Immune System; Protective Agents
PubMed: 33923766
DOI: 10.3390/nu13041324 -
Molecular Oncology Nov 2021Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs)...
Individuals with Fanconi anemia (FA), a rare genetic bone marrow failure syndrome, have an increased risk of young-onset head and neck squamous cell carcinomas (SCCs) and esophageal SCC. The FA DNA repair pathway is activated upon DNA damage induced by acetaldehyde, a chief alcohol metabolite and one of the major carcinogens in humans. However, the molecular basis of acetaldehyde-induced genomic instability in SCCs of the head and neck and of the esophagus in FA remains elusive. Here, we report the effects of acetaldehyde on replication stress response in esophageal epithelial cells (keratinocytes). Acetaldehyde-exposed esophageal keratinocytes displayed accumulation of DNA damage foci consisting of 53BP1 and BRCA1. At physiologically relevant concentrations, acetaldehyde activated the ATR-Chk1 pathway, leading to S- and G2/M-phase delay with accumulation of the FA complementation group D2 protein (FANCD2) at the sites of DNA synthesis, suggesting that acetaldehyde impedes replication fork progression. Consistently, depletion of the replication fork protection protein Timeless led to elevated DNA damage upon acetaldehyde exposure. Furthermore, FANCD2 depletion exacerbated replication abnormalities, elevated DNA damage, and led to apoptotic cell death, indicating that FANCD2 prevents acetaldehyde-induced genomic instability in esophageal keratinocytes. These observations contribute to our understanding of the mechanisms that drive genomic instability in FA patients and alcohol-related carcinogenesis, thereby providing a translational implication in the development of more effective therapies for SCCs.
Topics: Acetaldehyde; DNA Damage; DNA Repair; DNA Replication; Esophagus; Fanconi Anemia; Fanconi Anemia Complementation Group D2 Protein; Genomic Instability; Humans; Keratinocytes
PubMed: 34328261
DOI: 10.1002/1878-0261.13072 -
Advances in Experimental Medicine and... 2018Excessive consumption of alcohol is a leading cause of lifestyle-induced morbidity and mortality worldwide. Although long-term alcohol abuse has been shown to be... (Review)
Review
Excessive consumption of alcohol is a leading cause of lifestyle-induced morbidity and mortality worldwide. Although long-term alcohol abuse has been shown to be detrimental to the liver, brain and many other organs, our understanding of the exact molecular mechanisms by which this occurs is still limited. In tissues, ethanol is metabolized to acetaldehyde (mainly by alcohol dehydrogenase and cytochrome p450 2E1) and subsequently to acetic acid by aldehyde dehydrogenases. Intracellular generation of free radicals and depletion of the antioxidant glutathione (GSH) are believed to be key steps involved in the cellular pathogenic events caused by ethanol. With continued excessive alcohol consumption, further tissue damage can result from the production of cellular protein and DNA adducts caused by accumulating ethanol-derived aldehydes. Much of our understanding about the pathophysiological consequences of ethanol metabolism comes from genetically-engineered mouse models of ethanol-induced tissue injury. In this review, we provide an update on the current understanding of important mouse models in which ethanol-metabolizing and GSH-synthesizing enzymes have been manipulated to investigate alcohol-induced disease.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Animals; Cytochrome P-450 CYP2E1; Disease Models, Animal; Ethanol; Mice; Neoplasms
PubMed: 30362100
DOI: 10.1007/978-3-319-98788-0_14 -
Scientific Reports Apr 2020Recent evidence suggests that e-cigarette users tend to change their puffing behaviors when using e-liquids with reduced nicotine concentrations by taking longer and... (Clinical Trial)
Clinical Trial
Recent evidence suggests that e-cigarette users tend to change their puffing behaviors when using e-liquids with reduced nicotine concentrations by taking longer and more frequent puffs. Using puffing regimens modelled on puffing topography data from 19 experienced e-cigarette users who switched between 18 and 6 mg/mL e-liquids with and without power adjustments, differences in daily exposure to carbonyl compounds and estimated changes in cancer risk were assessed by production of aerosols generated using a smoking machine and analyzed using gas and liquid chromatography. Significant differences across conditions were found for formaldehyde and acetaldehyde (p < 0.01). Switching from a higher to a lower nicotine concentration was associated with greater exposure regardless of whether power settings were fixed or adjustable which is likely due to increased liquid consumption under lower nicotine concentration settings. Daily exposure for formaldehyde and acetaldehyde was higher for 17/19 participants when using low (6 mg/mL) compared with high (18 mg/mL) nicotine e-liquid concentration when power was fixed. When power adjustments were permitted, formaldehyde and acetaldehyde levels were higher respectively for 16/19 and 14/19 participants with the use of 6 compared with 18 mg/mL nicotine e-liquid.
Topics: Acetaldehyde; Aerosols; Carcinogens; Electronic Nicotine Delivery Systems; Formaldehyde; Humans; Neoplasms; Nicotine; Risk Factors
PubMed: 32300142
DOI: 10.1038/s41598-020-63292-1 -
Brazilian Journal of Microbiology :... 2016In this study a natural culture medium that mimics the synthetic yeast peptone glucose medium used for yeast fermentations was designed to screen and select yeasts...
In this study a natural culture medium that mimics the synthetic yeast peptone glucose medium used for yeast fermentations was designed to screen and select yeasts capable of producing high levels of diacetyl and acetaldehyde. The presence of whey powder and sodium citrate in the medium along with manganese and magnesium sulfate enhanced both biomass and aroma development. A total of 52 yeasts strains were cultivated in two different culture media, namely, yeast peptone glucose medium and yeast acetaldehyde-diacetyl medium. The initial screening of the strains was based on the qualitative reaction of the acetaldehyde with Schiff's reagent (violet color) and diacetyl with Brady's reagent (yellow precipitate). The fermented culture media of 10 yeast strains were subsequently analyzed by gas chromatography to quantify the concentration of acetaldehyde and diacetyl synthesized. Total titratable acidity values indicated that a total titratable acidity of 5.5°SH, implying culture medium at basic pH, was more favorable for the acetaldehyde biosynthesis using strain D15 (Candida lipolytica; 96.05mgL acetaldehyde) while a total titratable acidity value of 7°SH facilitated diacetyl flavor synthesis by strain D38 (Candida globosa; 3.58mgL diacetyl). Importantly, the results presented here suggest that this can be potentially used in the baking industry.
Topics: Acetaldehyde; Diacetyl; Energy Metabolism; Fermentation; Metabolome; Metabolomics; Yeasts
PubMed: 27528084
DOI: 10.1016/j.bjm.2016.07.005