-
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 -
Biomedical Papers of the Medical... Mar 2016Alcohol variants such as ethanol and methanol are simple organic compounds widely used in foods, pharmaceuticals, chemical synthesis, etc. Both are becoming an emerging... (Review)
Review
BACKGROUND
Alcohol variants such as ethanol and methanol are simple organic compounds widely used in foods, pharmaceuticals, chemical synthesis, etc. Both are becoming an emerging health problem; abuse of ethanol containing beverages can lead to disparate health problems and methanol is highly toxic and unfit for consumption.
METHODS AND RESULTS
This review summarizes the basic knowledge about ethanol and methanol toxicity, the effect mechanism on the body, the current care of poisoned individuals and the implication of alcohols in the development of diseases. Alcohol related dementia, stroke, metabolic syndrome and hepatitis are discussed as well. Besides ethanol, methanol toxicity and its biodegradation pathways are addressed.
CONCLUSIONS
The impact of ethanol and methanol on the body is shown as case reports, along with a discussion on the possible implication of alcohol in Alzheimer's disease and antidotal therapy for methanol poisoning. The role of ethanol in cancer and degenerative disorders seems to be underestimated given the current knowledge. Treatment in case of poisoning is another issue that remains unresolved even though effective protocols and drugs exist.
Topics: Alcohol Dehydrogenase; Alcoholic Beverages; Alcoholism; Aldehyde Dehydrogenase; Antidotes; Ethanol; Humans; Methanol; Receptors, Cell Surface
PubMed: 26006090
DOI: 10.5507/bp.2015.023 -
Current Psychiatry Reports Mar 2019We review the search for genetic variants that affect the risk for alcohol dependence and alcohol consumption. (Review)
Review
PURPOSE OF REVIEW
We review the search for genetic variants that affect the risk for alcohol dependence and alcohol consumption.
RECENT FINDINGS
Variations in genes affecting alcohol metabolism (ADH1B, ALDH2) are protective against both alcohol dependence and excessive consumption, but different variants are found in different populations. There are different patterns of risk variants for alcohol dependence vs. consumption. Variants for alcohol dependence, but not consumption, are associated with risk for other psychiatric illnesses. ADH1B and ALDH2 strongly affect both consumption and dependence. Variations in many other genes affect both consumption and dependence-or one or the other of these traits-but individual effect sizes are small. Evidence for other specific genes that affect dependence is not yet strong. Most current knowledge derives from studies of European-ancestry populations, and large studies of carefully phenotyped subjects from different populations are needed to understand the genetic contributions to alcohol consumption and alcohol use disorders.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Aldehyde Dehydrogenase, Mitochondrial; Humans
PubMed: 30852706
DOI: 10.1007/s11920-019-1008-1 -
Current Biology : CB Mar 2023Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex...
Several molecules can extend healthspan and lifespan across organisms. However, most are upstream signaling hubs or transcription factors orchestrating complex anti-aging programs. Therefore, these molecules point to but do not reveal the fundamental mechanisms driving longevity. Instead, downstream effectors that are necessary and sufficient to promote longevity across conditions or organisms may reveal the fundamental anti-aging drivers. Toward this goal, we searched for effectors acting downstream of the transcription factor EB (TFEB), known as HLH-30 in C. elegans, because TFEB/HLH-30 is necessary across anti-aging interventions and its overexpression is sufficient to extend C. elegans lifespan and reduce biomarkers of aging in mammals including humans. As a result, we present an alcohol-dehydrogenase-mediated anti-aging response (AMAR) that is essential for C. elegans longevity driven by HLH-30 overexpression, caloric restriction, mTOR inhibition, and insulin-signaling deficiency. The sole overexpression of ADH-1 is sufficient to activate AMAR, which extends healthspan and lifespan by reducing the levels of glycerol-an age-associated and aging-promoting alcohol. Adh1 overexpression is also sufficient to promote longevity in yeast, and adh-1 orthologs are induced in calorically restricted mice and humans, hinting at ADH-1 acting as an anti-aging effector across phyla.
Topics: Humans; Animals; Mice; Longevity; Caenorhabditis elegans; Alcohol Dehydrogenase; Caenorhabditis elegans Proteins; Aging; Mammals; Basic Helix-Loop-Helix Transcription Factors
PubMed: 36805847
DOI: 10.1016/j.cub.2023.01.059 -
Clinical and Experimental Medicine May 2017According to International Agency for Research on Cancer, ethanol and acetaldehyde belong to group 1 of human carcinogens. The accurate mechanism by which alcohol... (Review)
Review
According to International Agency for Research on Cancer, ethanol and acetaldehyde belong to group 1 of human carcinogens. The accurate mechanism by which alcohol consumption enhances carcinogenesis is still unexplained. Alcohol is oxidized primarily by alcohol dehydrogenase (ADH) to acetaldehyde, a substance capable of initiating carcinogenesis by forming adducts with proteins and DNA and causing mutations. Next, acetaldehyde is metabolized by aldehyde dehydrogenase (ALDH) to acetate. In tissues of many cancers, we can observe significantly higher activity of total alcohol dehydrogenase with any change in aldehyde dehydrogenase activity in comparison with healthy cells. Moreover, in malignant diseases of digestive system, significantly increased activity of ADH isoenzymes class I, III and IV was found. The gynecological, brain and renal cancers exhibit increased activity of class I ADH. ADH and ALDH can play also a crucial regulatory role in initiation and progression of malignant diseases by participation in retinoic acid synthesis and elimination of toxic acetaldehyde. Besides, changes of enzymes activities in tumor cells are reflected in serum of cancer patients, which create the possibilities of application ADH isoenzymes as cancer markers.
Topics: Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Biomarkers; Humans; Neoplasms; Serum
PubMed: 26886278
DOI: 10.1007/s10238-016-0408-3 -
The Journal of Organic Chemistry Aug 2023We report on novel chemoenzymatic routes toward tenofovir using low-cost starting materials and commercial or homemade enzyme preparations as biocatalysts. The...
We report on novel chemoenzymatic routes toward tenofovir using low-cost starting materials and commercial or homemade enzyme preparations as biocatalysts. The biocatalytic key step was accomplished either via stereoselective reduction using an alcohol dehydrogenase or via kinetic resolution using a lipase. By employing a suspension of immobilized lipase from (Amano PS-IM) in a mixture of vinyl acetate and toluene, the desired ()-ester (99% ee) was obtained on a 500 mg scale (60 mM) in 47% yield. Alternatively, stereoselective reduction of 1-(6-chloro-9-purin-9-yl) propan-2-one (84 mg, 100 mM) catalyzed by lyophilized cells harboring recombinant alcohol dehydrogenase (ADH) from (/Lk-ADH Prince) allowed one to reach quantitative conversion, 86% yield and excellent optical purity (>99% ee) of the corresponding ()-alcohol. The key ()-intermediate was transformed into tenofovir through "one-pot" aminolysis-hydrolysis of ()-acetate in NH-saturated methanol, alkylation of the resulting ()-alcohol with tosylated diethyl(hydroxymethyl) phosphonate, and bromotrimethylsilane (TMSBr)-mediated cleavage of the formed phosphonate ester into the free phosphonic acid. The elaborated enzymatic strategy could be applicable in the asymmetric synthesis of tenofovir prodrug derivatives, including 5'-disoproxil fumarate (TDF, Viread) and 5'-alafenamide (TAF, Vemlidy). The molecular basis of the stereoselectivity of the employed ADHs was revealed by molecular docking studies.
Topics: Tenofovir; Alcohol Dehydrogenase; Escherichia coli; Molecular Docking Simulation; Alanine; Organophosphonates; Lipase; Anti-HIV Agents
PubMed: 37467462
DOI: 10.1021/acs.joc.3c01005 -
Archiwum Medycyny Sadowej I Kryminologii 2016Alcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment... (Review)
Review
Alcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic background of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabolism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase; Humans; Polymorphism, Single Nucleotide; Risk Factors
PubMed: 28453170
DOI: 10.5114/amsik.2016.66401 -
The Journal of Biological Chemistry Oct 2014The role of evolutionary pressure on the chemical step catalyzed by enzymes is somewhat enigmatic, in part because chemistry is not rate-limiting for many optimized... (Review)
Review
The role of evolutionary pressure on the chemical step catalyzed by enzymes is somewhat enigmatic, in part because chemistry is not rate-limiting for many optimized systems. Herein, we present studies that examine various aspects of the evolutionary relationship between protein dynamics and the chemical step in two paradigmatic enzyme families, dihydrofolate reductases and alcohol dehydrogenases. Molecular details of both convergent and divergent evolution are beginning to emerge. The findings suggest that protein dynamics across an entire enzyme can play a role in adaptation to differing physiological conditions. The growing tool kit of kinetics, kinetic isotope effects, molecular biology, biophysics, and bioinformatics provides means to link evolutionary changes in structure-dynamics function to the vibrational and conformational states of each protein.
Topics: Alcohol Dehydrogenase; Animals; Bacterial Proteins; Biocatalysis; Catalytic Domain; Evolution, Molecular; Humans; Kinetics; Models, Chemical; Tetrahydrofolate Dehydrogenase
PubMed: 25210031
DOI: 10.1074/jbc.R114.565515 -
Proceedings of the National Academy of... Jun 2016The presence of intervening sequences, termed introns, is a defining characteristic of eukaryotic nuclear genomes. Once transcribed into pre-mRNA, these introns must be...
The presence of intervening sequences, termed introns, is a defining characteristic of eukaryotic nuclear genomes. Once transcribed into pre-mRNA, these introns must be removed within the spliceosome before export of the processed mRNA to the cytoplasm, where it is translated into protein. Although intron loss has been demonstrated experimentally, several mysteries remain regarding the origin and propagation of introns. Indeed, documented evidence of gain of an intron has only been suggested by phylogenetic analyses. We report the use of a strategy that detects selected intron gain and loss events. We have experimentally verified, to our knowledge, the first demonstrations of intron transposition in any organism. From our screen, we detected two separate intron gain events characterized by the perfect transposition of a reporter intron into the yeast genes RPL8B and ADH2, respectively. We show that the newly acquired introns are able to be removed from their respective pre-mRNAs by the spliceosome. Additionally, the novel allele, RPL8Bint, is functional when overexpressed within the genome in a strain lacking the Rpl8 paralogue RPL8A, demonstrating that the gene targeted for intronogenesis is functional.
Topics: Alcohol Dehydrogenase; Evolution, Molecular; Genes, Fungal; Genes, Reporter; Introns; Models, Genetic; Phylogeny; RNA, Fungal; RNA, Messenger; Ribosomal Proteins; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Spliceosomes
PubMed: 27217561
DOI: 10.1073/pnas.1605113113 -
BMC Genomics Oct 2023Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited.
METHODS
We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake.
RESULTS
We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke).
CONCLUSION
This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.
Topics: Humans; Male; Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; East Asian People; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Flushing
PubMed: 37875790
DOI: 10.1186/s12864-023-09721-7