Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Levels of RNA, mRNA and separation of ribosomal proteins from control and ethanol treated rat liver, showed no change in total RNA content, but poly(A+)mRNA was reduced significantly in ethanolic rats. Ribosomal proteins S2, S3a, S3b, S4, L3, L4, L4a, L10a and L15 were found substantially reduced in experimental rat livers. This study suggests decrease in poly(A+) mRNA coupled with loss of ribosomal proteins must be responsible for decreased protein synthesis in chronic alcoholism.
Mol Cell Biochem 1992 Oct 07
PMID:Effect of ethanol on hepatic ribosomal proteins and mRNA. 144 59

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.
Mol Aspects Med 1988
PMID:Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. 306 25

Authors critically review current data about biochemical-physiological factors mediating genetic predisposition to alcoholism. Results of genetic investigation of the ethanol and acetaldehyde metabolism and the facts about enzyme polymorphism of systems of the ethanol biotransformation and genetic polymorphism of particular enzymes are summarized. Data about possible determinants of nervous system sensitivity to ethanol action are considered. The investigation of genetic basis of phenomena imminent to alcoholism by use of laboratory animals is discussed.
Mol Gen Mikrobiol Virusol 1987 Apr
PMID:[Alcoholism and heredity: biological basis of the predisposition to alcoholism]. 329 66

Weight paired (approximately 200 g) Long-Evans male rats (n = 48) were divided into two groups: an ethanol-consuming (A) and a water-consuming control (C) group. Ethanol concentration was raised incrementally over a one month period until it reached 25% (v/v). The diet of group C was regulated calorically to minimize differences between the two groups in the consumption of protein, fat, and carbohydrate. Half the members of each group were killed 12 weeks after initiating the special diets for the determination of myocardial electrolyte and water distributions and uptake of a tracer normally restricted to the extracellular space (ECS). The remaining rats were returned to a normal diet (recovery groups AR and CR) and killed 8 weeks later. Left ventricular tissue and plasma were analyzed for Na, K, Ca, and Mg; ECS was assessed in the same samples by tracer distribution and morphometric methods. Comparison of the myocardial [35S]sulfate space as a function of equilibration duration in the four groups indicates that the tracer leaks into the cellular compartment of alcoholic rats, suggesting that myocardial sarcolemmal permeability is increased in alcoholism. This interpretation is supported by the finding that all cations studied either were (Na, Ca) or tended to be (K, Mg) displaced down their respective electrochemical gradients. It is concluded that a reversible, non-selective sarcolemmal leakiness may be one of the earliest effects of alcoholism on the heart, eventually resulting in a redistribution of myocardial electrolytes and associated alterations of electrical, metabolic, and contractile activities.
J Mol Cell Cardiol 1983 Feb
PMID:In vivo effects of ethanol on the rat myocardium: evidence for a reversible, non-specific increase of sarcolemmal permeability. 685 57

Recent studies have shown that the alpha-hydroxyethyl radical (CH3CHOH), a metabolite of ethanol, is produced in vitro and in vivo. We report studies that establish the immunogenicity of alpha-hydroxyethyl radical-derived protein adducts. Rat liver microsomes incubated in the presence of [14C]ethanol and NADPH (under aerobic conditions) incorporate 14C into acid-stable adducts. Incorporation was markedly inhibited by the free-radical scavenger alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone. Rabbits immunized with rat liver microsomes that had been preincubated with ethanol and NADPH generated antibodies that recognized polylysine-acetaldehyde adducts and adducts formed by incubation of proteins with an alpha-hydroxyethyl radical-generating system (ethanol plus H2O2 plus Fe2+). Rabbits immunized with microsomes that had been preincubated with ethanol and NADPH plus alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone generated antibodies that recognized polylysine-acetaldehyde adducts. However, their reactivity against alpha-hydroxyethyl-derived protein epitopes was greatly reduced or was virtually abolished. Data indicate that microsomes metabolizing ethanol generate two types of adducts, acetaldehyde-derived adducts and alpha-hydroxyethyl radical-derived adducts, both of which are immunogenic. Immunization of rabbits with alpha-hydroxyethyl-bovine serum albumin adducts led to the production of antibodies that recognized alpha-hydroxyethyl-rabbit serum albumin adducts but did not recognize the native protein. Chronic alcohol feeding of rats led to the production of antibodies that recognized alpha-hydroxyethyl-rat serum albumin adducts but did not recognize rat serum albumin. The study (i) indicates that alpha-hydroxyethyl radical-derived protein adducts are immunogenic, (ii) supports earlier work that proposed that alpha-hydroxyethyl radicals generated in different systems bind covalently to proteins, and (iii) demonstrates the formation of antibodies to alpha-hydroxyethyl-derived protein adducts after chronic alcohol ingestion in vivo. The findings may have implications in the identification of chronic alcohol abuse and the pathogenesis of alcohol-induced organ damage.
Mol Pharmacol 1994 Oct
PMID:Ethanol-derived immunoreactive species formed by free radical mechanisms. 796 61

The pivotal role that G proteins play in transmembrane signal transduction is highlighted by the rapidly expanding list of receptors and effector molecules that are coupled through G proteins. G proteins are poised to allow discrimination and diversification of cellular signals into the cytosolic milieu. The utilization of an evolutionarily conserved "GTPase clock" by G proteins, offers insight into the fundamental role these proteins play in biology. Knowledge of the implication of altered expression or function of G proteins in human disease is now emerging. It is not surprising that deficiency or expression of altered forms of these important proteins can lead to global or restricted metabolic disturbances, depending upon the distribution and role of the G protein. Human disorders, including heart failure, alcoholism, endocrine abnormalities, and neoplasia, are now recognized as due in part to altered expression or function of G proteins.
Prog Nucleic Acid Res Mol Biol 1994
PMID:Signal-transducing G proteins: basic and clinical implications. 801 26

The receptors for tetrahydrocannabinol, the active ingredient of marijuana, have been identified. A microsatellite polymorphism (AAT)n at the cannabinoid CB1 (brain) receptor gene (CNR1) consists of 9 alleles. Since the cannabinoid system is part of the reward pathway we examined the hypothesis that genetic variants of the CNR1 gene might be associated with susceptibility to alcohol or drug dependence. The study consisted of 92 subjects on an Addiction Treatment Unit (ATU) and 114 controls. All were non-Hispanic Caucasians. The ATU subjects were screened for all types of substance dependence using the Diagnostic Interview Schedule (DIS), and for a variety of substance abuse symptoms using the Addiction Severity Index (ASI). Since inspection of the distribution of alleles in controls vs i.v. drug use showed a decrease in the frequency of the 4 allele, and the < 4 alleles were rare, the alleles were divided into two groups, < 5 and < or = 5, and three genotypes < 5/< 5, heterozygotes, and > or =/> or = 5. When all variables were subjected to factor analysis, factor 1 showed a clustering of drug dependence variables and factor 2 of alcohol dependence variables. By ANOVA only factor 1 showed significant differences by genotype consistent with a model where homozygosity for the > or = 5 repeat alleles showed the greatest effect. The number of i.v. drugs used was significantly greater for those carrying the > or =/> or = 5 genotype than for other genotypes (P = 0.005). The association with specific types of drug dependence was greatest for cocaine, amphetamine, and cannabis dependence. The results are consistent with a role of cannabinoid receptors in the modulation of dopamine and cannabinoid reward pathways. Independent studies should be designed to further confirm the hypothesis that cannabinoid receptors may contribute to the susceptibility to drug abuse.
Mol Psychiatry 1997 Mar
PMID:Cannabinoid receptor gene (CNR1): association with i.v. drug use. 1082 38

Increasing our knowledge about the major addictive diseases, opiate and cocaine addiction and alcoholism, is of great importance from a public, as well as personal health perspective. Each disease is associated with profound and negative impacts on physical and mental health and also each has devastating social and economic consequences. Each of these addictive diseases has been associated with major infectious diseases including AIDS, hepatitis B, C, D and G, either through parenteral or sexual transmission. Since 1967, we have addressed the research question related to our early hypotheses on the development of an addiction, that atypical responsitivity to stress and stressors may play a central role in the acquisition and persistence of, and relapse to, drug abuse. We have been conducting studies both in humans and in animal models focused on the role of disruption of the stress responsive hypothalamic-pituitary-adrenal axis in opiate addiction, cocaine dependency and alcoholism. We also have conducted studies of the role of the endogenous opioid system in modulation of this axis, as well as the interaction of the endogenous opioid system with the dopaminergic system and other neurotransmitter and neuropeptides related to the reinforcing effects of drugs of abuse.
Mol Psychiatry 1996 Jul
PMID:Opiates, opioids and addiction. 911 48

The effects of prolonged ethanol exposure on excitatory amino acid receptor stimulated nitric oxide (NO) formation were examined in primary rat cortical neuronal cultures. Chronic ethanol (4 days, 100 mM) potentiated N-methyl-D-aspartate (NMDA)-stimulated NO formation as determined by measuring the conversion of [3H]arginine to [3H]citrulline. In contrast, chronic ethanol had no effect on NO formation stimulated by kainate, alpha-amino-3-hydroxy-5-methyl-4-isoxalonepropionic acid, or the calcium ionophore ionomycin. Potassium chloride-stimulated NO formation was also enhanced by chronic ethanol treatment, but this effect was not seen in the presence of the ionotropic glutamate receptor antagonists MK-801 and 6-cyano-7-nitroquinoxaline-2,3-dione. Immunoblot analysis of expression of NR1, NR2A, and NR2B receptor subunits showed no difference between control and chronic ethanol-treated cultures. In support of this apparent lack of change in receptor density, there was no difference in the specific binding of 125I-MK-801 between control and chronic ethanol-treated groups. These results demonstrate that prolonged ethanol exposure selectively enhanced NMDA receptor-stimulated NO formation, which may play an important role in alcohol dependence, withdrawal, and alcohol-associated brain damage. These results also suggest that chronic ethanol-induced increases in NMDA receptor function may not be due to a simple increase in the number of NMDA receptors or change in NMDA receptor subunit composition but may instead reflect more complicated and subtle changes.
Mol Pharmacol 1997 May
PMID:Chronic ethanol increases N-methyl-D-aspartate-stimulated nitric oxide formation but not receptor density in cultured cortical neurons. 914 11

Only in the past decade has a role of heredity in substance abuse been established as a result of extensive twin and family studies. More recently, several candidate genes have been investigated for their possible role in alcoholism and cocaine abuse. Specific genetic factors in opioid substance abuse have not been investigated in man, although animal studies suggest that quantitative trait loci (QTLs) can be identified that predispose mice both to morphine and alcohol preference. Central dopaminergic pathways figure prominently in drug-mediated reinforcement suggesting that dopamine receptors are likely candiadates for association with substance abuse in man. In addition, we recently reported an association between a human personality trait, Novelty Seeking and the long alleles (represented chiefly by the 7-repeat) of the D4 dopamine receptor (D4DR) exon III polymorphism. The personality trait of Novelty Seeking is also more pronounced in substance abusers, who score higher in this dimension than control subjects. The twin role of dopamine receptors in mediating Novelty Seeking and drugreinforcement prompted us to examine a group of Israeli heroin addicts for prevalence of the D4DR repeat polymorphism. We now show that the 7-repeat allele is significantly over-represented in the opioid-dependent cohort and confers a relative risk of 2.46. To our knowledge this is the first report of an association between a specific genetic polymorphism and opioid addiction.
Mol Psychiatry 1997 May
PMID:Excess dopamine D4 receptor (D4DR) exon III seven repeat allele in opioid-dependent subjects. 915 90


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