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Alcoholism, Clinical and Experimental... Dec 2018Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic... (Review)
Review
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol [EtOH]) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
Topics: Alcohol Dehydrogenase; Alcoholism; Aldehyde Dehydrogenase, Mitochondrial; Humans; Linkage Disequilibrium
PubMed: 30320893
DOI: 10.1111/acer.13904 -
AIDS and Behavior Feb 2020We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the...
We contrast three types of abstinence: quit after alcohol associated problems (Q-AP), quit for other reasons (Q-OR), and lifetime abstainer (LTA). We summarized the characteristics of people living with HIV (PLWH), and matched uninfected individuals, by levels of alcohol use and types of abstinence. We then identified factors that differentiate abstinence and determined whether the association with an alcohol biomarker or a genetic polymorphism is improved by differentiating abstinence. Among abstainers, 34% of PLWH and 38% of uninfected were Q-AP; 53% and 53% were Q-OR; and 12% and 10% were LTA. Logistic regression models found smoking, alcohol, cocaine, and hepatitis C increased odds of Q-AP, whereas smoking and marijuana decreased odds of LTA. Differentiating types of abstinence improved association. Q-APs and LTAs can be readily differentiated by an alcohol biomarker and genetic polymorphism. Differentiating type of abstinence may enhance understanding of alcohol health effects.
Topics: Adult; Alcohol Abstinence; Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Biomarkers; Case-Control Studies; Female; Glycerophospholipids; HIV Infections; Humans; Male; Middle Aged; Polymorphism, Genetic; Self Report; Smoking
PubMed: 31435887
DOI: 10.1007/s10461-019-02638-x -
International Journal of Molecular... May 2017Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is... (Review)
Review
Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is metabolized by alcohol dehydrogenases (ADH), catalase or cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then further oxidized to acetate by aldehyde dehydrogenase (ALDH). Acetaldehyde has been classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen to humans. The acetaldehyde level in the stomach and colon is locally influenced by gastric colonization by or colonic microbes, as well as polymorphisms in the genes encoding tissue alcohol metabolizing enzymes, especially ALDH2. Alcohol stimulates the uptake of carcinogens and their metabolism and also changes the composition of enteric microbes in a way to enhance the aldehyde level. Alcohol also undergoes chemical coupling to membrane phospholipids and disrupts organization of tight junctions, leading to nuclear translocation of β-catenin and ZONAB, which may contributes to regulation of genes involved in proliferation, invasion and metastasis. Alcohol also generates reactive oxygen species (ROS) by suppressing the expression of antioxidant and cytoprotective enzymes and inducing expression of CYP2E1 which contribute to the metabolic activation of chemical carcinogens. Besides exerting genotoxic effects by directly damaging DNA, ROS can activates signaling molecules involved in inflammation, metastasis and angiogenesis. In addition, alcohol consumption induces folate deficiency, which may result in aberrant DNA methylation profiles, thereby influencing cancer-related gene expression.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Alcohol Drinking; Aldehyde Dehydrogenase; Animals; Carcinogenesis; Colon; Colonic Neoplasms; Cytochrome P-450 CYP2E1; Epigenesis, Genetic; Ethanol; Gastric Mucosa; Humans; Polymorphism, Genetic; Stomach; Stomach Neoplasms
PubMed: 28538665
DOI: 10.3390/ijms18061116 -
Current Drug Metabolism 2016It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile. (Review)
Review
BACKGROUND
It is well known that ethanol can cause significant morbidity and mortality, and much of the related toxic effects can be explained by its metabolic profile.
OBJECTIVE
This work performs a complete review of the metabolism of ethanol focusing on both major and minor metabolites.
METHOD
An exhaustive literature search was carried out using textual and structural queries for ethanol and related known metabolizing enzymes and metabolites.
RESULTS
The main pathway of metabolism is catalyzed by cytosolic alcohol dehydrogenase, which exhibits multiple isoenzymes and genetic polymorphisms with clinical and forensic implications. Another two oxidative routes, the highly inducible CYP2E1 system and peroxisomal catalase may acquire relevance under specific circumstances. In addition to oxidative metabolism, ethanol also originates minor metabolites such as ethyl glucuronide, ethyl sulfate, ethyl phosphate, ethyl nitrite, phosphatidylethanol and fatty acid ethyl esters. These metabolites represent alternative biomarkers since they can be detected several hours or days after ethanol exposure.
CONCLUSION
It is expected that knowing the metabolomics of ethanol may provide additional insights to better understand the toxicological effects and the variability of dose response.
Topics: Acetaldehyde; Alcohol Dehydrogenase; Aldehyde Dehydrogenase; Aldehyde Oxidase; Animals; Biomarkers; Catalase; Cytochrome P-450 CYP2E1; Ethanol; Fatty Acids; Gastrointestinal Microbiome; Glucuronates; Glycerophospholipids; Humans; Isoenzymes; Liver; Metabolomics; Nitric Oxide Synthase; Nitrites; Oxidation-Reduction; Sulfuric Acid Esters; Xanthine Oxidase
PubMed: 26805730
DOI: 10.2174/1389200217666160125113806 -
Applied and Environmental Microbiology Dec 2022Alkanes produced by microorganisms are expected to be an alternative to fossil fuels as an energy source. Microbial synthesis of alkanes involves the formation of fatty...
Alkanes produced by microorganisms are expected to be an alternative to fossil fuels as an energy source. Microbial synthesis of alkanes involves the formation of fatty aldehydes via fatty acyl coenzyme A (acyl-CoA) intermediates derived from fatty acid metabolism, followed by aldehyde decarbonylation to generate alkanes. Advancements in metabolic engineering have enabled the construction of such pathways in various microorganisms, including Escherichia coli. However, endogenous aldehyde reductases in the host microorganisms are highly active in converting fatty aldehydes to fatty alcohols, limiting the substrate pool for alkane production. To reuse the alcohol by-product, a screening of fatty alcohol-assimilating microorganisms was conducted, and a bacterial strain, sp. strain 7-4, was found to convert 1-tetradecanol to tetradecanal. From this strain, an alcohol dehydrogenase, PsADH, was purified and found to be involved in 1-tetradecanol-oxidizing reaction. Subsequent heterologous expression of the gene in E. coli was conducted, and recombinant PsADH was purified for a series of biochemical characterizations, including cofactors, optimal reaction conditions, and kinetic parameters. Furthermore, direct alkane production from alcohol was achieved in E. coli by coexpressing PsADH with a cyanobacterial aldehyde-deformylating oxygenase and a reducing system, including ferredoxin and ferredoxin reductase, from Nostoc punctiforme PCC73102. The alcohol-aldehyde-alkane synthetic route established in this study will provide a new approach to utilizing fatty alcohols for the production of alkane biofuel. Alcohol dehydrogenases are a group of enzymes found in many organisms. Unfortunately, studies on these enzymes mainly focus on their activities toward short-chain alcohols. In this study, we discovered an alcohol dehydrogenase, PsADH, from the bacterium sp. 7-4, which can oxidize 1-tetradecanol to tetradecanal. The medium-chain aldehyde products generated by this enzyme can serve as the substrate of aldehyde-deformylating oxygenase to produce alkanes. The enzyme found in this study can be applied to the biosynthetic pathway involving the formation of medium-chain aldehydes to produce alkanes and other valuable compounds.
Topics: Escherichia coli; Alcohol Dehydrogenase; Ferredoxins; Aldehydes; Alcohols; Alkanes; Fatty Acids; Fatty Alcohols; Oxygenases
PubMed: 36416567
DOI: 10.1128/aem.01264-22 -
Plant Signaling & Behavior 2019(alcohol dehydrogenase 1) was involved in plant growth and development and responded to various stresses. We published a cold-induced alcohol dehydrogenase 1 gene from...
(alcohol dehydrogenase 1) was involved in plant growth and development and responded to various stresses. We published a cold-induced alcohol dehydrogenase 1 gene from , which exists 43 unique amino acids. Here, we confirmed that overexpression of in and tobacco significantly improved cold shock tolerance through electrolyte leakage, semi-lethal temperature, phenotypic and survival analysis. These results indicate that CbADH1 is the candidate gene to improve the ability of plant freezing resistance, and it has great application value.
Topics: Acclimatization; Adaptation, Physiological; Alcohol Dehydrogenase; Arabidopsis; Brassicaceae; Cold Temperature; Gene Expression Regulation, Plant; Homozygote; Plants, Genetically Modified; Seedlings; Nicotiana
PubMed: 31056000
DOI: 10.1080/15592324.2019.1612680 -
Nutrients Nov 2021Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against intoxication, only inconclusive data are...
Silymarin is known for its hepatoprotective effects. Although there is solid evidence for its protective effects against intoxication, only inconclusive data are available for alcoholic liver damage. Since silymarin flavonolignans have metal-chelating activity, we hypothesized that silymarin may influence alcoholic liver damage by inhibiting zinc-containing alcohol dehydrogenase (ADH). Therefore, we tested the zinc-chelating activity of pure silymarin flavonolignans and their effect on yeast and equine ADH. The most active compounds were also tested on bovine glutamate dehydrogenase, an enzyme blocked by zinc ions. Of the six flavonolignans tested, only 2,3-dehydroderivatives (2,3-dehydrosilybin and 2,3-dehydrosilychristin) significantly chelated zinc ions. Their effect on yeast ADH was modest but stronger than that of the clinically used ADH inhibitor fomepizole. In contrast, fomepizole strongly blocked mammalian (equine) ADH. 2,3-Dehydrosilybin at low micromolar concentrations also partially inhibited this enzyme. These results were confirmed by in silico docking of active dehydroflavonolignans with equine ADH. Glutamate dehydrogenase activity was decreased by zinc ions in a concentration-dependent manner, and this inhibition was abolished by a standard zinc chelating agent. In contrast, 2,3-dehydroflavonolignans blocked the enzyme both in the absence and presence of zinc ions. Therefore, 2,3-dehydrosilybin might have a biologically relevant inhibitory effect on ADH and glutamate dehydrogenase.
Topics: Alcohol Dehydrogenase; Animals; Chelating Agents; Flavonolignans; Glutamate Dehydrogenase; Horses; Silybin; Silymarin; Yeasts; Zinc
PubMed: 34959790
DOI: 10.3390/nu13124238 -
American Journal of Medical Genetics.... Mar 2018The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702,... (Review)
Review
The ADH1B (Alcohol Dehydrogenase 1B (class I), Beta Polypeptide) gene and its best-known functional alleles, Arg48His (rs1229984, ADH1B*2) and Arg370Cys (rs2066702, ADH1B*3), have been investigated in relation to many phenotypic traits; most frequently including alcohol metabolism and alcohol drinking behaviors, but also human evolution, liver function, cancer, and, recently, the comprehensive human phenome. To understand ADH1B functions and consequences, we provide here a bioinformatic analysis of its gene regulation and molecular functions, literature review of studies focused on this gene, and a discussion regarding future research perspectives. Certain ADH1B alleles have large effects on alcohol metabolism, and this relationship particularly encourages further investigations in relation to alcoholism and alcohol-associated cancer to understand better the mechanisms by which alcohol metabolism contributes to alcohol abuse and carcinogenesis. We also observed that ADH1B has complex mechanisms that regulate its expression across multiple human tissues, and these may be involved in cardiac and metabolic traits. Evolutionary data strongly suggest that the selection signatures at the ADH1B locus are primarily related to effects other than those on alcohol metabolism. This is also supported by the involvement of ADH1B in multiple molecular pathways and by the findings of our recent phenome-wide association study. Accordingly, future studies should also investigate other functions of ADH1B potentially relevant for the human phenome. © 2017 Wiley Periodicals, Inc.
Topics: Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Alleles; Genotype; Humans; Neoplasms; Phenotype
PubMed: 28349588
DOI: 10.1002/ajmg.b.32523 -
Alcohol Research : Current Reviews 2016Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic... (Review)
Review
Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)--particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles--have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person's alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity).
Topics: Adult Survivors of Child Adverse Events; Black or African American; Alcohol Dehydrogenase; Alcohol Drinking; Alcoholism; Aldehyde Dehydrogenase; Alleles; Asian; Culture; Ethanol; Ethnicity; Family; Gene-Environment Interaction; Genetic Predisposition to Disease; Genetic Variation; Humans; Religion; Social Norms; White People
PubMed: 27163368
DOI: No ID Found -
Journal of Alzheimer's Disease : JAD 2022Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide...
BACKGROUND
Mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10) is necessary for brain cognitive function, but its studies were confounded by reports of Aβ-peptide binding alcohol dehydrogenase (ABAD), formerly endoplasmic reticulum-associated Aβ-peptide binding protein (ERAB), for two decades so long as ABAD serves as the alternative term of 17β-HSD10.
OBJECTIVE
To determine whether those ABAD reports are true or false, even if they were published in prestigious journals.
METHODS
6xHis-tagged 17β-HSD10 was prepared and characterized by well-established experimental procedures.
RESULTS
The N-terminal 6xHis tag did not significantly interfere with the dehydrogenase activities of 17β-HSD10, but the kinetic constants of its 3-hydroxyacyl-CoA dehydrogenase activity are drastically distinct from those of ABAD, and it was not involved in ketone body metabolism as previously reported for ABAD. Furthermore, it was impossible to measure its generalized alcohol dehydrogenase activities underlying the concept of ABAD because the experimental procedures described in ABAD reports violated basic chemical and/or biochemical principles. More incredibly, both authors and journals had not yet agreed to make any corrigenda of ABAD reports.
CONCLUSION
Brain 17β-HSD10 plays a key role in neurosteroid metabolism and further studies in this area may lead to potential treatments of neurodegeneration including AD.
Topics: 17-Hydroxysteroid Dehydrogenases; 3-Hydroxyacyl CoA Dehydrogenases; Alcohol Dehydrogenase; Alzheimer Disease; Amyloid beta-Peptides; Coenzyme A; Humans
PubMed: 35786658
DOI: 10.3233/JAD-220481