Main ethanol metabolizing alcohol dehydrogenases (ADH I and ADH IV): biochemical functions and the physiological manifestation

Ашмарин, И. П.; Danilova, R. A.; Obukhova, M. F.; Moskvitina, T. A.; Prosorovsky, V.N

doi:10.1016/s0014-5793(00)02229-8

Cited by 17 publications

(19 citation statements)

References 24 publications

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“…11 With a low K m (o5 mM) for ethanol, these enzymes play a major role in ethanol metabolism. There are several polymorphic variants of ADH1, which differ in their efficiency for ethanol oxidation.…”

Section: Ethanol Metabolism: An Updatementioning

confidence: 99%

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism

Quertemont

2004

Mol Psychiatry

152

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Acetaldehyde, the first product of ethanol metabolism, has been speculated to be involved in many pharmacological and behavioral effects of ethanol. In particular, acetaldehyde has been suggested to contribute to alcohol abuse and alcoholism. In the present paper, we review current data on the role of acetaldehyde and ethanol metabolism in alcohol consumption and abuse. Ethanol metabolism involves several enzymes. Whereas alcohol dehydrogenase metabolizes the bulk of ethanol within the liver, other enzymes, such as cytochrome P4502E1 and catalase, also contributes to the production of acetaldehyde from ethanol oxidation. In turn, acetaldehyde is metabolized by the enzyme aldehyde dehydrogenase. In animal studies, acetaldehyde is mainly reinforcing particularly when injected directly into the brain. In humans, genetic polymorphisms of the enzymes alcohol dehydrogenase and aldehyde dehydrogenase are also associated with alcohol drinking habits and the incidence of alcohol abuse. From these human genetic studies, it has been concluded that blood acetaldehyde accumulation induces unpleasant effects that prevent further alcohol drinking. It is therefore speculated that acetaldehyde exerts opposite hedonic effects depending on the localization of its accumulation. In the periphery, acetaldehyde is primarily aversive, whereas brain acetaldehyde is mainly reinforcing. However, the peripheral effects of acetaldehyde might also be dependent upon its peak blood concentrations and its rate of accumulation, with a narrow range of blood acetaldehyde concentrations being reinforcing.

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Section: Ethanol Metabolism: An Updatementioning

confidence: 99%

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism

Quertemont

2004

Mol Psychiatry

152

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“…The best characterised functions of ADH are protection against excess of endogenous alcohols, products of lipid peroxidation and some exogenous xenobiotics [2]. It was also found that isoenzymes of class I ADH participate in bioamine, prostaglandin and retinoid acid metabolism [3]. Moreover class III of ADH catalyses the oxidation of S-hydroxymethylglutathione much more effectively than ethanol [4].…”

Section: Introductionmentioning

confidence: 99%

The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in breast cancer

et al. 2006

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Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) play a significant role in the metabolism of many biological substances. ADH participates in the metabolism of ethanol, retinoic acid, lipid peroxidation products, leukotriene and glutathione metabolism. ALDH is responsible for oxidation of acetaldehyde and other aldehydes and metabolism of histamine and retinoic acid. The aim of this study was to compare the metabolism in breast cancer cells and normal breast parenchyma by measuring ADH isoenzymes and ALDH activities in these tissues. Total ADH activity was measured by a photometric method with p-nitrosodimethylaniline (NDMA) as a substrate. For the measurement of the activity of ALDH and class I and II isoenzymes of ADH we employed the fluorometric methods, with class-specific fluorogenic substrates. The activity of class III alcohol dehydrogenase was detected by the photometric method with n-octanol and class IV with m-nitrobenzaldehyde as substrates. The samples were taken surgically during resection of breast carcinoma from 75 women. The activity of the class I ADH isoenzyme was significantly lower in breast cancer cells than in healthy tissues. The other tested classes of ADH had a tendency for higher levels of activity in cancer cells than in normal mammary tissue. The activity of total ADH and ALDH was also not significantly lower in the cancer cells. The decrease of activity of class I ADH isoenzyme in breast cancer tissues may be a factor of some disorders in metabolic pathways with participation of these isoenzymes that can lead to carcinogenesis.

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“…Primarily expressed in the liver [13] , they encode subunits that form a homo-or heterodimer [1] , which accounts for 70% of hepatic ethanol oxidation [14,15] . ADH1B and ADH1C are polymorphic, with three and two alleles [16] , respectively, defined by the amino acids encoded by single nucleotide polymorphisms (SNPs).…”

Section: Metabolic Genesmentioning

confidence: 99%

Using a Pharmacokinetic Model to Relate an Individual’s Susceptibility to Alcohol Dependence to Genotypes

Mustavich¹,

Miller²,

Kídd³

et al. 2010

Hum Hered

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Background/Aims: Population-based studies have successfully identified genes affecting common diseases, but have not provided a molecular mechanism. We describe an approach for alcohol dependence connecting a mechanistic model at the molecular level with disease risk at the population level, and investigate how this model implies statistical gene-gene interactions that affect disease risk. Methods: We develop a pharmacokinetic model describing how genetic variations in ADH1B, ADH1C, ADH7, ALDH2, and TAS2R38 affect consumption behavior, and alcohol and acetaldehyde levels over time in various tissues of individuals with a particular genotype to predict their susceptibility to alcohol dependence. Results: We show that there is good agreement between the observed genotype/haplotype frequencies and those predicted by the model among cases and controls. Based on this framework, we show that we expect to observe statistical interactions among these genes for a reasonably large sample size when logistic regression models are used to relate genotype effects and disease risk. Conclusion: Our model exemplifies mechanistic modeling of how genes interact to influence an individual’s susceptibility to alcohol dependence. We anticipate that this general approach could also be applied to study other diseases at the molecular level.

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Main ethanol metabolizing alcohol dehydrogenases (ADH I and ADH IV): biochemical functions and the physiological manifestation

Cited by 17 publications

References 24 publications

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism

Genetic polymorphism in ethanol metabolism: acetaldehyde contribution to alcohol abuse and alcoholism

The activity of class I, II, III and IV alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in breast cancer

Using a Pharmacokinetic Model to Relate an Individual’s Susceptibility to Alcohol Dependence to Genotypes

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