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Mechanism Of Protection Against Alcoholism By An Alcohol Dehydrogenase Polymorphism: Development Of An Animal Model
Mario Rivera-Meza, M. Quintanilla, L. Tampier, C. V. Mura, A. Sapag, Y. Israel
Published 2010 · Biology, Medicine
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Humans who carry a point mutation in the gene coding for alcohol dehydrogenase‐lB (ADH1B*2; Arg47His) are markedly protected against alcoholism. Although this mutation results in a 100‐fold increase in enzyme activity, it has not been reported to cause higher levels of acetaldehyde, a metabolite of ethanol known to deter alcohol intake. Hence, the mechanism by which this mutation confers protection against alcoholism is unknown. To study this protective effect, the wild‐type rat cDNA encoding rADH‐47Arg was mutated to encode rADH‐47His, mimicking the human mutation. The mutated cDNA was incorporated into an adenoviral vector and administered to genetically selected alcohol‐preferring rats. The Vmax of rADH‐47His was 6‐fold higher (P<0.001) than that of the wild‐type rADH‐47Arg. Animals transduced with rAdh‐47His showed a 90% (P<0.01) increase in liver ADH activity and a 50% reduction (P< 0.001) in voluntary ethanol intake. In animals transduced with rAdh‐47His, administration of ethanol (1g/kg) produced a short‐lived increase of arterial blood acetaldehyde concentration to levels that were 3.5‐ to 5‐fold greater than those in animals transduced with the wild‐type rAdh‐47Arg vector or with a noncoding vector. This brief increase (burst) in arterial acetaldehyde concentration after ethanol ingestion may constitute the mechanism by which humans carrying the ADH1B*2 allele are protected against alcoholism.—Rivera‐Meza, M., Quin‐tanilla, M. E., Tampier, L., Mura, C. V., Sapag, A., Israel, Y. Mechanism of protection against alcoholism by an alcohol dehydrogenase polymorphism: development of an animal model. FASEB J. 24, 266–274 (2010). www.fasebj.org
This paper references
Sex differences, alcohol dehydrogenase, acet273 ADH POLYMORPHISM AND ETHANOL CONSUMPTION aldehyde burst, and aversion to ethanol in the rat: a systems perspective
M. E. Quintanilla (2007)
Site - directed
S. N. Ho (1989)
Nutrient-Sensitive Mitochondrial NAD+ Levels Dictate Cell Survival
Hongying Yang (2007)
Involvement of genetic polymorphism of alcohol and aldehyde dehydrogenases in individual variation of alcohol metabolism.
Y. Mizoi (1994)
Sexual dimorphic expression of ADH in rat liver: importance of the hypothalamic-pituitary-liver axis.
F. Simon (2002)
Complete amino acid sequence of rat liver alcohol dehydrogenase deduced from the cDNA sequence. Gene
D. W. Crabb (1986)
World Health Organization (2007) Problems related to alcohol consumption. Second report of WHO Expert Committee
Interaction between the functional polymorphisms of the alcohol-metabolism genes in protection against alcoholism.
C. Chen (1999)
REVIEW: The UChA and UChB rat lines: metabolic and genetic differences influencing ethanol intake
M. Quintanilla (2006)
The determination of enzyme inhibitor constants.
M. Dixon (1953)
Thirty-two years of selection of rats by ethanol preference: UChA and UChB strains.
J. Mardones (1983)
Lifelong elimination of hyperbilirubinemia in the Gunn rat with a single injection of helper-dependent adenoviral vector.
Gabriele Toietta (2005)
Genetic selection for high and low alcohol consumption in a limited-access paradigm.
A. Lê (2001)
Tolerance to disulfiram induced by chronic alcohol intake in the rat.
L. Tampier (2008)
Association of the ADH2*2 allele with reduced ethanol consumption in Jewish men in Israel: a pilot study.
Y. Neumark (1998)
Expression and kinetic characterization of variants of human beta 1 beta 1 alcohol dehydrogenase containing substitutions at amino acid 47.
T. Hurley (1990)
Ischemic preconditioning induces XRCC1, DNA polymerase-beta, and DNA ligase III and correlates with enhanced base excision repair.
N. Li (2007)
Alcohol-induced redox changes in the liver of the spontaneously hypertensive rat: effect of chronic ethanol treatment.
S. Wahid (1981)
Interactive effects of lifetime alcohol consumption and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks
Y. Chen (2006)
Amino Acid Substitutions at Position 47 of Human BIBl and ( B 2 P 2 Alcohol Dehydrogenases Affect Hydride Transfer and Coenzyme Dissociation Rate Constants *
Amino acid substitutions at position 47 of human beta 1 beta 1 and beta 2 beta 2 alcohol dehydrogenases affect hydride transfer and coenzyme dissociation rate constants.
C. Stone (1993)
The genetics of alcoholism in Polynesians: alcohol and aldehyde dehydrogenase genotypes in young men.
G. Chambers (2002)
Problems related to alcohol consumption
H. R. Thomasson (2007)
Revitalization of the AA and ANA rat lines: effects on some line characteristics.
L. Hilakivi (1984)
Associations of variations in alcohol dehydrogenase genes with the level of response to alcohol in non-Asians.
Nicole C E Duranceaux (2006)
DNA‐dependent protein kinase is involved in heat shock protein‐mediated accumulation of hypoxia‐inducible factor‐1α in hypoxic preconditioned HepG2 cells
M. Kang (2008)
A simplified system for generating recombinant adenoviruses.
T. He (1998)
POSSIBLE PROTECTIVE ROLE AGAINST ALCOHOLISM FOR ALDEHYDE DEHYDROGENASE ISOZYME DEFICIENCY IN JAPAN
S. Harada (1982)
The Determination of Enzyme Dissociation Constants
H. Lineweaver (1934)
Complete amino acid sequence of rat liver alcohol dehydrogenase deduced from the cDNA sequence.
D. Crabb (1986)
Polymorphism of ethanol-metabolism genes and alcoholism: correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences.
Y. Chen (2009)
Dose-specific effects of alcohol on the lifespan of mice and the possible relevance to man.
W. Schmidt (1987)
Alcohol sensitivity related to polymorphism of alcohol-metabolizing enzymes in Japanese
Y. Mizoi (1983)
Alcohol consumption by orientals in North America is predicted largely by a single gene
G. Tu (1995)
Blood acetaldehyde concentration gradient between hepatic and antecubital venous blood in ethanol‐intoxicated alcoholics and controls*
H. Nuutinen (1984)
Targeting the mitochondria to augment myocardial protection.
D. Schwartz (2008)
Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men.
H. Thomasson (1991)
Major genetic components underlying alcoholism in Korean population.
Daejin Kim (2008)
Hormesis: the dose-response revolution.
E. Calabrese (2003)
Tolerance to disulfiram by chronic alcohol intake in the rat
L. Tampier (2008)
Site-directed mutagenesis by overlap extension using the polymerase chain reaction.
S. Ho (1989)
Evaluation of the concentration and bioactivity of adenovirus vectors for gene therapy.
N. Mittereder (1996)
Eliciting the Low-Activity Aldehyde Dehydrogenase Asian Phenotype by an Antisense Mechanism Results in an Aversion to Ethanol
E. Garver (2001)
Pharmacokinetic and pharmacodynamic basis for partial protection against alcoholism in Asians, heterozygous for the variant ALDH2*2 gene allele
Giia-Sheun Peng (2007)
The determination of enzyme inhibitor
M. Dixon (1953)
Involvement of Glutamate 399 and Lysine 192 in the Mechanism of Human Liver Mitochondrial Aldehyde Dehydrogenase*
L. Ni (1997)
Global burden of disease from alcohol, illicit drugs and tobacco.
J. Rehm (2006)
Effect of alcohol on the lactate/pyruvate ratio of recently injured adults
F. Lecky (2002)
Expression and kinetic characterization of variants of human 1 1 alcohol dehydrogenase containing substitutions at amino acid
T. D. Hurley (1990)
Genetic polymorphism of alcohol dehydrogenase in europeans: TheADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1
E. Borrás (2000)
Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal and stomach cancers in Japanese alcoholics.
A. Yokoyama (2001)
by overlap extension using the polymerase chain reaction
H. Lineweaver (1934)
Modulation of alcohol dehydrogenase and ethanol metabolism by sex hormones in the spontaneously hypertensive rat. Effect of chronic ethanol administration.
G. Rachamin (1980)
Administration of helper-dependent adenoviral vectors and sequential delivery of different vector serotype for long-term liver-directed gene transfer in baboons.
N. Morral (1999)
Sex differences, alcohol dehydrogenase, acetaldehyde burst, and aversion to ethanol in the rat: a systems perspective.
M. Quintanilla (2007)
Genetic associations of alcohol dehydrogenase with alcohol use disorders and endophenotypes in white college students.
T. Wall (2005)
Do alcohol‐metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?
E. Zintzaras (2006)
Polymorphisms of ethanol metabolizing enzyme genes and alcoholism.
S. Higuchi (1994)
Expression of Coxsackie adenovirus receptor and alphav-integrin does not correlate with adenovector targeting in vivo indicating anatomical vector barriers
H. Fechner (1999)
Pharmacogenetic models of alcoholism.
T. K. Li (1995)
The simultaneous measurement of nicotinamide adenine dinucleotide and related compounds by liquid chromatography/electrospray ionization tandem mass spectrometry.
K. Yamada (2006)
Evidence for beneficial low level radiation effects and radiation hormesis.
L. Feinendegen (2005)
Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population.
Y. Neumark (2004)
Hydrogen transfer between ethanol molecules during oxidoreduction in vivo.
T. Cronholm (1985)
Acetaldehyde utilization in Drosophila: an example of hormesis
P. Parsons (1989)
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De Novo-Synthesized Retinoic Acid in Ovarian Antral Follicles Enhances FSH-Mediated Ovarian Follicular Cell Differentiation and Female Fertility.
T. Kawai (2016)
Gene specific modifications unravel ethanol and acetaldehyde actions
Y. Israel (2013)
Development of Industrial Brewing Yeast with Low Acetaldehyde Production and Improved Flavor Stability
Jinjing Wang (2013)
Shortened telomeres in individuals with abuse in alcohol consumption
S. Pavanello (2011)
Rat animal models for screening medications to treat alcohol use disorders
R. Bell (2017)
Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration.
M. Matsumoto (2011)
Genetics of alcohol dependence
M. Kimura (2011)
Genetic and environmental influences on ethanol consumption: perspectives from preclinical research.
R. Pautassi (2010)
Establishment of steady-state metabolism of ethanol in perfused rat liver: the quantitative analysis using kinetic mechanism-based rate equations of alcohol dehydrogenase.
Chung-Tay Yao (2010)
ALDH2*2 but not ADH1B*2 is a causative variant gene allele for Asian alcohol flushing after a low-dose challenge: correlation of the pharmacokinetic and pharmacodynamic findings
Giia-Sheun Peng (2014)
Functional Polymorphisms of Alcohol Metabolism Genes and their Protection Against Alcoholism via Gene Therapy: A Systematic Review
O. Tzeng (2018)
Identificación de nuevos genes diana del receptor nuclear FXR
Elena Pedraz Cuesta (2012)
Acetaldehyde burst protection of ADH1B*2 against alcoholism: an additional hormesis protection against esophageal cancers following alcohol consumption?
Y. Israel (2011)
The genetics of alcohol dependence
M. Rietschel (2013)
Natural alcohol exposure: is ethanol the main substrate for alcohol dehydrogenases in animals?
Aída Hernández-Tobías (2011)
Ethanol as a prodrug: brain metabolism of ethanol mediates its reinforcing effects.
E. Karahanian (2011)
Excessive alcohol consumption increases mortality in later life: a genetic analysis of the health in men cohort study
O. Almeida (2017)
Fenofibrate -a PPARα agonist- increases alcohol dehydrogenase levels in the liver: implications for its possible use as an ethanol-aversive drug.
D. Muñoz (2019)
Piecing together the puzzle of acetaldehyde as a neuroactive agent
M. Correa (2012)
The C‐terminal extension of Mycobacterium tuberculosis Hsp16.3 regulates its oligomerization, subunit exchange dynamics and chaperone function
A. K. Panda (2017)
Reduction of ethanol consumption in alcohol-preferring rats by dual expression gene transfer.
Mario Rivera-Meza (2012)
Fenofibrate--a lipid-lowering drug--reduces voluntary alcohol drinking in rats.
E. Karahanian (2014)
Developmental lead exposure induces opposite effects on ethanol intake and locomotion in response to central vs. systemic cyanamide administration.
M. Mattalloni (2017)
Elucidating the biological basis for the reinforcing actions of alcohol in the mesolimbic dopamine system: the role of active metabolites of alcohol
G. Deehan (2013)
Long‐term inhibition of ethanol intake by the administration of an aldehyde dehydrogenase‐2 (ALDH2)‐coding lentiviral vector into the ventral tegmental area of rats
E. Karahanian (2015)
Eating, Drinking, Smoking and Cancer Prevention: A Focus on Acetaldehyde
R. Rajendram (2013)
Genetics of Substance Use Disorders.
Cassie Yu (2016)
Anxiogenic and stress-inducing effects of peripherally administered acetaldehyde in mice: Similarities with the disulfiram–ethanol reaction
Miguel A Escrig (2012)
The genetics and epigenetics of substance misuse : an investigation into life stress and reward processing in adolescence
C. P. Wong (2014)
ADH1B polymorphism, alcohol consumption, and binge drinking in Slavic Caucasians: results from the Czech HAPIEE study.
J. Hubáček (2012)
Common single nucleotide variants underlying drug addiction: more than a decade of research
Kora-Mareen Bühler (2015)
Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.
Gaeun Kang (2014)See more